Melanin concentrating hormone receptor ligands: substituted 1-benzyl-4-aryl piperazine analogues

ABSTRACT

Melanin concentrating hormone receptor ligands (especially 1-benzyl-4-aryl-piperazines, 1-benzyl-4-aryl-piperidines and related compounds), capable of modulating MCH receptor activity, are provided. Such ligands may be used to modulate MCH binding to MCH receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of metabolic, feeding and sexual disorders in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting MCH receptors (e.g., receptor localization studies).

FIELD OF THE INVENTION

This invention relates generally to 1-benzyl-4-aryl piperazine andpiperidine analogues. Certain such analogues are modulators of melaninconcentrating hormone receptor. The invention further relates to the useof such compounds for treating a variety of metabolic, eating and sexualdisorders, and as probes for the detection and localization of MCHreceptors.

BACKGROUND OF THE INVENTION

Melanin concentrating hormone, or MCH, is a cyclic 19 amino acidneuropeptide that functions as a regulator of food intake and energybalance. MCH is produced in the hypothalamus of many vertebrate species,including humans, and serves as a neurotransmitter in the lateral andposterior hypothalamus. Both of these regions have been associated withbehaviors such as eating, drinking, aggression and sexual behavior. MCHis also produced at various peripheral sites, including thegastrointestinal tract and testis.

The postulated role of MCH in feeding behavior and body weight has beenconfirmed by the finding that I.C.V. injection of MCH into the lateralventricle of the hypothalamus increases caloric consumption in rats oversimilarly treated control animals. Furthermore, rats having the oblobgenotype exhibit a 50-80% increase in MCH mRNA expression as compared toleaner ob/+ genotype mice. MCH knockout mice are leaner than theirMCH-producing siblings due to hypophagia and an increased metabolicrate.

MCH activity is mediated via binding to specific receptors. The MCH typeI receptor (MCHR1) is a 353 amino acid, 7-transmembrane, alpha-helical,G-coupled protein receptor, first reported by Lakaye, et al. (BBA (1998)1401:216-220). MCHR1 has also been known as SLC-1. Immunohistochemistrystudies of rat brain sections indicate that the MCHR1 receptor is widelyexpressed in the brain. MCHR1 receptor expression has been found in theolfactory tubercle, cerebral cortex, substantia nigra, basal forebrainCA1, CA2, and CA3 field of the hippocampus, amygdala, and in nuclei inthe hypothalamus, thalamus, midbrain and hindbrain. Strong signals havebeen observed in the ventromedial and dorsomedial nuclei of thehypothalamus, two areas of the brain known to be involved in feedingbehavior. Upon binding MCH, MCHR1 receptors expressed in HEK 293 cellmediate a dose dependent release of intracellular calcium. Cellsexpressing MCH receptors have also been shown to exhibit a pertussistoxin sensitive dose-dependent inhibition of forskolin-elevated cyclicAMP, indicating that the receptor couples to a G_(i/o) G-protein alphasubunit.

Recently, a second MCH receptor (MCHR2) has been identified (An et al.,Proc. Natl. Acad. Sci. USA (2001) 98:7576-7581; Sailer et al., Proc.Natl. Acad. Sci. USA (2001) 98:7564-7569; Hill et al., J. Biol. Chem.(2001) 276:20125-20129; Mori et al., Biochem. Biophys. Res. Commun.(2001) 283:1013-1018). MCHR2 has an overall amino acid identity of morethan 30% with MCHR1, and is detected specifically in most regions of thebrain, with an expression pattern similar to that of MCHR1.

Because MCH is an important regulator of food intake and energy balance,agents capable of modulating MCH receptor activity, especially MCHR1,are highly desirable for the treatment of obesity, eating disorders(e.g., bulimia and anorexia), sexual disorders (e.g., anorgasmic orpsychogenic impotence) and metabolic disorders, such as diabetes. Smallmolecule, non-peptide antagonists of MCH receptors would be ofparticular value for such therapies. The present invention fulfills thisneed, and provides further related advantages.

SUMMARY OF THE INVENTION

The present invention provides MCH receptor modulators that inhibit orenhance MCH binding to MCH receptor and/or MCH receptor activity. Suchmodulators comprise a substituted 1-benzyl-4-aryl piperazine orpiperidine analogue that exhibits a K_(i) of 1 micromolar or less in anMCH receptor ligand binding assay and/or an MCH receptor-mediated signaltransduction assay (calcium mobilization assay), and is characterized bythe formula:

or a pharmaceutically acceptable salt thereof, wherein:

-   V is a bond or —(C═O)—;-   W is nitrogen, CH, COH or CCN;-   X is halogen, hydroxy, nitro, cyano, —COOH, oxo and groups of the    formula L-M;-   Y and Z are each independently: (i) CH, (ii) nitrogen, or (iii)    joined with R₅ to form a carbocyclic or heterocyclic ring comprising    W and V and having from 5 to 8 ring members, with the proviso that Y    and Z are not both nitrogen;-   n is 1 or 2;-   R₁ and R₂ are each independently selected from: hydrogen, halogen,    hydroxy, nitro, cyano, —COOH, oxo and groups of the formula L-M,    with the proviso that if R₁ and R₂ are hydrogen, then V is —(C═O)—;-   R₃ is: (i) selected from hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl and    halo(C₁-C₆)alkyl; or    -   (ii) joined with one or both of R₆ and R₁₀ to form a carbocyclic        or heterocyclic group having one ring or two fused rings,        wherein each ring contains from 5 to 8 ring members and 0, 1 or        2 heteroatoms independently chosen from oxygen, nitrogen and        sulfur;-   R₄ is hydrogen, (C₁-C₆)alkyl or halo(C₁-C₆)alkyl;-   R₅ is (i) independently selected at each occurrence from hydrogen,    halogen, hydroxy, nitro, cyano, amino, oxo, (C₁-C₆)alkyl,    (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,    halo(C₁-C₆)alkoxy, mono- and di(C₁-C₆)alkylamino, and    amino(C₁-C₆)alkyl; or    -   (ii) joined with R₆, Y or Z to form a carbocyclic or        heterocyclic ring having from 5 to 8 ring members;-   R₆ is: (i) selected from hydrogen, halogen, hydroxy, nitro, cyano,    amino, oxo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,    (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, mono- and    di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl), or    -   (ii) joined with R₃ or R₅ to form a carbocyclic or heterocyclic        group as described above;-   R₇ is: (i) selected from hydrogen, halogen, hydroxy, nitro, cyano,    —COOH, oxo; and groups of the formula L-M; or    -   (ii) joined with R₈ or R₁₂ to form a fused 5- or 6-membered        carbocyclic or heterocyclic group;-   R₈ is: (i) selected from hydrogen, halogen, hydroxy, nitro, cyano,    —COOH, oxo; and groups of the formula L-M; or    -   (ii) joined with R₇ or R₁₁ to form a fused 5- to 10-member        carbocyclic or heterocyclic group;-   U is N, O or CR₉;-   T is N, O or CR₁₀;-   R₉ is: (i) selected from hydrogen, halogen, hydroxy, nitro, cyano,    —COOH, oxo, and groups of the formula L-M; or    -   (ii) joined with R₁₀ or R₁₁ to form a fused 5- to 10-member        carbocyclic or heterocyclic group;-   R₁₀ is: (i) selected from hydrogen, halogen, hydroxy, nitro, cyano,    —COOH, oxo, and groups of the formula L-M; or    -   (ii) joined with R₃, R₈ or R₉ to form a carbocyclic or        heterocyclic group;-   R₁₁ is: (i) selected from hydrogen, halogen, hydroxy, nitro, cyano,    —COOH, oxo, and groups of the formula L-M; or    -   (ii) joined with one or both of R₈ and R₉ to form a fused 5- to        10-member carbocyclic or heterocyclic group;-   R₁₂ is: (i) independently selected at each occurrence from hydrogen,    halogen, hydroxy, nitro, cyano, amino, oxo, (C₁-C₆)alkyl,    (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,    halo(C₁-C₆)alkoxy, mono- and di(C₁-C₆)alkylamino, and    amino(C₁-C₆)alkyl; or    -   (ii) joined with R₇ to form a fused carbocyclic or heterocyclic        ring;-   L is independently selected at each occurrence from a bond, —NR₁₁—    —O—, —SO₂—, —SO₂NH—, C(═O)NR₁₁— and NR₁₁C(═O)—, wherein R₁₁ is    independently selected at each occurrence from hydrogen,    (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, and halo(C₁-C₆)alkyl;    and-   M is independently selected at each occurrence from hydrogen,    (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halo(C₁-C₆)alkyl,    amino(C₁-C₆alkyl) and 5 to 10-membered carbocycles;    with the proviso that if R₁₁ is halogen and V is a bond, then at    least one of R₁₀, R₃ and R₄ is not hydrogen.

The present invention further provides MCH receptor modulators,comprising one or more compounds as described above associated with(i.e., linked to or combined with) at least one additional component,such as a drug, targeting moiety or carrier.

Within further aspects, the present invention provides pharmaceuticalcompositions comprising a compound or modulator as described above incombination with a physiologically acceptable carrier or excipient.Within certain embodiments, a pharmaceutical composition provided hereinmay further comprise one or more additional active agents (i.e., drugs).Pharmaceutical compositions provided herein may be formulated, forexample, as an injectible fluid, an aerosol, a cream, a gel, a pill, acapsule, a syrup or a transdermal patch.

The present invention further provides, within other aspects, methodsfor treating a disease or disorder associated with MCH receptoractivation, comprising administering to a patient in need of suchtreatment an effective amount of a compound or modulator as describedabove. Such diseases and disorders include, for example, eatingdisorders (e.g., obesity and bulimia nervosa), sexual disorders,diabetes, heart disease and stroke. The compound or modulator may beadministered orally, or via another means such as intranasally,intravenously or topically. Within certain embodiments, the patient is ahuman, companion animal or livestock animal.

Within further aspects, the present invention provides compounds asdescribed above, wherein the compounds are radiolabeled.

Methods are provided, within other aspects, for determining the presenceor absence of MCH receptor in a sample, comprising the steps of: (a)contacting a sample with an agent comprising a compound as describedabove under conditions that permit binding of the agent to MCH receptor;and (b) detecting a level of agent bound to MCH receptor. Within certainembodiments, the agent is a radiolabeled compound, and the step ofdetection comprises the steps of: (i) separating unbound agent frombound agent; and (ii) determining an amount of bound agent in thesample. Detection may be achieved, for example, using autoradiography.

The present invention further provides, within other aspects, methodsfor modulating binding of ligand to MCH receptor. Certain such methodsare performed in vitro, and comprise contacting MCH receptor with acompound or modulator as described above under conditions and in anamount sufficient to detectably modulate MCH binding to MCH receptor.Other such methods may be performed in vivo, and comprise contactingcells expressing MCH receptor with a compound or modulator as describedabove in an amount sufficient to detectably modulate MCH binding tocells expressing a cloned MCH receptor in vitro. Modulation of MCHbinding may be determined, for example, using a ligand binding assay asprovided herein.

Methods are further provided for modulating binding of MCH to MCHreceptor in a patient, comprising administering to a patient (i.e., ahuman or non-human animal) a compound or modulator as described above.Patients may include, for example, companion animals such as dogs.

Within certain embodiments of the above methods, the modulation isinhibition and/or the MCH receptor is a human MCH receptor.

Within further aspects, the present invention provides methods formodulating the signal-transducing activity of MCH receptor, comprisingcontacting an MCH receptor, either in vivo or in vitro, with asufficient amount of an MCH receptor modulator, under conditionssuitable for binding of MCH to MCH receptor. Preferably, the MCHreceptor is a MCH 1 receptor present in the hypothalamus.

Also provided by the present invention are packaged pharmaceuticalpreparations, comprising: (a) a pharmaceutical composition as describedabove in a container; and (b) instructions for using the composition totreat a patient suffering from a disease or disorder associated with MCHreceptor activation. Such disorders include, for example eatingdisorders (e.g., obesity and bulimia nervosa), sexual disorders,diabetes, heart disease and stroke.

These and other aspects of the present invention will become apparentupon reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention provides MCH receptor modulatorscomprising small molecule MCH receptor ligands that are substituted1-benzyl-4-aryl piperazine and piperidine analogues. Such modulators maybe used in vitro or in vivo, to inhibit or enhance MCH binding to MCHreceptors in a variety of contexts, as discussed in further detailbelow.

Terminology

Prior to setting forth the invention in detail, it may be helpful toprovide definitions of certain terms to be used herein. Compounds of thepresent invention are generally described using standard nomenclature.For compounds having asymmetric centers, it should be understood that(unless otherwise specified) all of the optical isomers and mixturesthereof are encompassed. In addition, compounds with carbon-carbondouble bonds may occur in Z- and E-forms, with all isomeric forms of thecompounds being included in the present invention. Where a compoundexists in various tautomeric forms, the invention is not limited to anyone of the specific tautomers, but rather includes all tautomeric forms.Certain compounds are described herein using a general formula thatincludes variables. Unless otherwise specified, each variable withinsuch a formula is defined independently of other variable, and anyvariable that occurs more than one time in Formula I is definedindependently at each occurrence. In addition, it will be apparent thatcombinations of substituents and/or variables are permissible only ifsuch combinations result in a stable compound.

As used herein, “(C₁-C₆)alkyl” refers to optionally substituted,straight or branched chain alkyl groups or cycloalkyl groups having 1-6carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl,n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl,hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, cyclopropyl, cyclopropylmethyland cyclohexyl. A (C₁-C₆)alkyl group may be bonded to an atom within amolecule of interest via any chemically suitable portion of the(C₁-C₆)alkyl group. Preferred alkyl groups include methyl, ethyl,propyl, butyl, cyclopropyl, cyclopropylmethyl, cyclopentyl andcyclohexyl. Particularly preferred alkyl groups are (C₁-C₄)alkyl groups,especially methyl and ethyl.

Similarly, “(C₂-C₆)alkenyl” refers to optionally substituted, straightor branched chain alkene groups or cycloalkene groups having 2 to 6carbon atoms, with (C₂-C₄)alkenyl groups preferred. Within an alkenylgroup, one or more unsaturated carbon-carbon double bonds are present,and may occur at any stable point along the chain (e.g., ethenyl, allyland isopropenyl). “(C₂-C₆)alkynyl” refers to straight or branched chainalkyne groups or cycloalkynyl groups having 2 to 6 carbon atoms, with(C₂-C₄) alkynyl groups preferred. Within an alkynyl group, one or moreunsaturated carbon-carbon triple bonds are present, and may occur at anystable point along the chain (e.g., ethynyl and propargyl). A “stablepoint” is bond that, when unsaturated, results in a chemically stablecompound (i.e., a compound that can be isolated, characterized andtested for biological activity).

By “(C₁-C₆)alkoxy,” in the present invention, is meant an optionallysubstituted alkyl group of 1 to 6 carbon atoms in a linear, branched orcycloalkyl arrangement attached via an oxygen bridge. (C₁-C₆)alkoxygroups include, for example, methoxy, ethoxy, propoxy, isopropoxy,n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy,isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.(C₁-C₄)alkoxy groups are generally preferred, especially ethoxy andmethoxy. Similarly, “(C₁-C₆)alkylthio” refers to an alkyl group of 1 to6 carbon atoms attached via a sulfur bridge.

“(C₂-C₆)alkanoyl” refers to an acyl group with 2 to 6 carbon atoms in alinear, branched or cycloalkyl arrangement. (C₂-C₄)alkanoyl groups aregenerally preferred.

“(C₂-C₆)alkanone” refers to a ketone substituent with 2 to 6 carbonatoms in a linear, branched or cyclic arrangement. (C₂-C₄)alkanonegroups are generally preferred.

The term “(C₁-C₆)alkoxycarbonyl” refers to an alkoxy substituent linkedvia a carbonyl. In other words, an alkoxycarbonyl substituent has thegeneral structure —C(═O)—O-alkyl.

“(C₂-C₆)alkylcarboxamido” refers to an alkyl substituent linked via acarboxamide group. In other words, an alkylcarboxamido substituent hasthe general structure —C(═O)—NH-alkyl.

“(C₂-C₆)alkylsulfonamido” refers to an alkyl substituent linked via asulfonamide group. In other words, an alkylcarboxamido substituent hasthe general structure —SO₂—NH-alkyl.

“(C₁-C₆)alkanoyloxy,” as used herein, refers to an alkanoyl group linkedvia an oxygen bridge. In other words, an alkanoyloxy group has thegeneral structure —O—C(═O)-alkyl. (C₁-C₄)alkanoyloxy groups aregenerally preferred.

The term “(C₁-C₆)carbonate” refers to an alkoxycarbonyl group linked viaan oxygen bridge. In other words, a carbonate group has the generalstructure —O—C(═O)—O-alkyl. (C₁-C₄)carbonate groups are generallypreferred.

Similarly, “(C₂-C₆)alkyl ether” refers to an ether substituent with 2 to6 carbon atoms, linked via a carbon-carbon bond. (C₂-C₄)alkylethergroups are preferred.

The term “(C₁-C₆)carbamate,” as used herein, refers to a group havingthe general structure —N—C(═O)—O-alkyl. (C₁-C₄)carbamate groups aregenerally preferred.

The term “oxo,” as used herein, refers to a keto (C═O) group. An oxogroup that is a substituent of a nonaromatic ring results in aconversion of —CH₂— to —C(═O)—. It will be apparent that theintroduction of an oxo substituent on an aromatic ring destroys thearomaticity.

The term “oxime” refers to a group of the structure:

If an oxime is designated as a substituent, the carbon atom is generallypart of the base structure, with only the ═NOH added. The carbon atom ofthe oxime may, of course, be a member of a carbocyclic or heterocyclicring. If a ring is aromatic, it will be apparent that the introductionof an oxime substituent destroys the aromaticity.

The term “halogen” includes fluorine, chlorine, bromine and iodine. A“haloalkyl” may be an optionally substituted, branched or straight-chainsaturated aliphatic hydrocarbon group, substituted with 1 or morehalogen atoms. “Halo(C₁-C₆)alkyl” groups have 1 to 6 carbon atoms;“halo(C₁-C₄)alkyl” groups have 1 to 4 carbon atoms. Examples ofhaloalkyl groups include, but are not limited to, mono-, di- ortri-fluoromethyl; mono-, di- or tri-chloromethyl; mono-, di-, tri-,tetra- or penta-fluoroethyl; and mono-, di-, tri-, tetra- orpenta-chloroethyl. Typical haloalkyl groups are trifluoromethyl anddifluoromethyl. Preferably not more than 5, and more preferably not morethan 3, haloalkyl groups are present in compounds provided herein. Theterm “haloalkoxy” refers to a haloalkyl group as defined above attachedvia an oxygen bridge. “Halo(C₁-C₆)alkoxy” groups have 1 to 6 carbonatoms.

A “substituent,” as used herein, refers to a molecular moiety that iscovalently bonded to an atom within a molecule of interest. For example,a “ring substituent” may be a moiety such as a halogen, alkyl group,alkoxy group, haloalkyl group or other group as discussed herein that iscovalently bonded to an atom (preferably a carbon or nitrogen atom) thatis a ring member. The term “substitution” refers to replacing a hydrogenatom in a molecular structure with a substituent as described above,such that the valence on the designated atom is not exceeded, and suchthat a chemically stable compound (i.e., a compound that can beisolated, characterized, and tested for biological activity) resultsfrom the substitution.

Groups that are “optionally substituted” are unsubstituted or aresubstituted by other than hydrogen at one or more available positions,typically 1, 2, 3 or 4 positions, by one or more substituentsindependently selected from halogen, cyano, nitro, oxo, oxime,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, hydroxy, amino, mono or di(C₁-C₆)alkyl amino,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, (C₁-C₆)alkanoyl, (C₁-C₆)alkanone,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)carbonate,(C₁-C₆)alkyl ether, (C₁-C₆)carbamate, —COOH, —CONH₂, mono- ordi-(C₁-C₈)alkylcarboxamido, —SO₂NH₂, mono and di(C₁-C₈)alkylsulfonamido,and carbocyclic and heterocyclic groups as described below. Preferably,an optionally substituted group is substituted with 0 to 5 independentlyselected substituents; more preferably 0 to 3 independently selectedsubstituents. Substituents may be located at any point(s) that result ina stable compound.

A dash (”-“) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

A “heteroatom,” as used herein, is oxygen, sulfur or nitrogen.

A “carbocycle” or “carbocyclic group” comprises at least one ring formedentirely by carbon-carbon bonds (i.e., a carbocyclic ring). Unlessotherwise specified, such ring(s) may be aromatic or non-aromatic(unsaturated, partially saturated or saturated), and are optionallysubstituted. The term “carbocyclic ring,” as used herein encompassesrings in which ring carbon atoms are unsubstituted or substituted asdescribed below. A carbocyclic group generally has from 1 to 3 fused orpendant carbocyclic rings, preferably one ring or two fused carbocyclicrings. Typically, each ring contains from 3 to 8 (preferably from 5 to7) ring members; carbocyclic groups comprising fused or pendant ringsystems typically contain from 9 to 14 members. A “ring member” is acarbon atom or heteroatom that is a part of a ring, and is directlybonded to two other such atoms. A phenyl or pyridyl group, for example,has 6 ring members, regardless of the number of atoms present withinring substituents. Representative examples of carbocyclic groups areoptionally substituted cycloalkyl groups (e.g., cyclopentane andcyclohexane), as well as aromatic groups such as optionally substitutedphenyl, benzyl, naphthyl, phenoxyl, benzoxyl and phenylethanonyl.Optional substitutions include those listed above. If a ring containsone or more substitutions, each substitution is selected independentlyof any other substitutions. (C₅-C₁₀)carbocyclic groups that contain 1carbocyclic ring or 2 fused carbocyclic rings (for a total of 5 to 10ring members), optionally substituted as described above, are preferred.

A “heterocycle” or “heterocyclic group” comprises at least one ring inwhich at least one ring atom is a heteroatom (i.e., N, O or S), and theremainder of the ring atoms are carbon (such a ring is referred to as aheterocyclic ring). Preferably, a heterocyclic group comprises 1-4heteroatoms; within certain embodiments, groups comprising 1 or 2heteroatoms are preferred. A heterocyclic group generally has from 1 to3 fused or pendant rings, preferably one ring or two fused rings, eachof which is optionally substituted. The term “heterocyclic ring,” asused herein encompasses rings in which ring carbon atoms are substitutedas described below. Each ring within a heterocyclic group isindependently aromatic or non-aromatic (unsaturated, partially saturatedor saturated). Typically, each ring contains from 3 to 8 ring members(preferably from 5 to 7 ring members); heterocyclic groups comprisingfused or pendant ring systems typically contain from 9 to 14 ringmembers. Heterocyclic groups may be optionally substituted with from 1to 5 substituents, each of which is independently selected from theoptional substituents indicated above. Unless otherwise specified, aheterocyclic group may be aromatic or nonaromatic (e.g., aheterocycloalkyl such as piperazine or diazepane). 3- to 10-memberedheterocyclic groups that contain 1 heterocyclic ring or 2 fused rings(at least one of which is heterocyclic; for a total of 3 to 10 ringmembers), optionally substituted as described above, are preferred, with5- to 10-membered heterocyclic groups (i.e., groups with from 5 to 10ring members and optional substitution(s)) particularly preferred.

Examples of heterocyclic groups include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothio-furanyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,benoztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, diazepanyl, dioxolanyl, dithiazinyl,dihydrofurotetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiadiazinyl, thiadiazolyl, thianthrenyl,thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiophenyl, triazinyl and xanthenyl. Within certain embodiments, pyridylrings are preferred. It will be apparent that any such heterocyclicgroups may be substituted with one or more substituents as describedabove.

The term “MCH receptor” refers to a protein comprising any MCH receptorsequence (i.e., a cellular protein that detectably binds MCH andmediates a dose dependent release of intracellular calcium).Naturally-occurring mammalian (especially human and monkey) MCH type 1or type 2 receptor sequences are generally preferred. An MCH receptormay consist entirely of an endogenous sequence, or may compriseadditional components (e.g., N-terminal leader sequence) that do notsubstantially inhibit the receptor's ability to bind MCH (i.e., at least50% of the binding affinity of the receptor for MCH is retained).Similarly, truncated MCH receptor sequences, or sequences containingamino acid deletions, substitutes, additions or modifications may beused (e.g., chimeric receptors), provided that MCH receptor bindingproperties are not substantially diminished (i.e., at least 50% of theendogenous MCH-binding affinity is retained). The binding affinity of acandidate MCH receptor for MCH may be evaluated using a standard ligandbinding assay as provided herein.

A “MCH receptor modulator,” also referred to herein as a “modulator,” isa compound that modulates (i.e., increases or decreases) MCH binding toone or more MCH receptors, as well as MCH receptor-mediated signaltransduction. In other words, a modulator may be a MCH receptor agonistor antagonist. Modulators provided herein comprise a compound that is asubstituted 1-benzyl-4-aryl piperazine or piperidine analogue having MCHreceptor modulating activity. A modulator may consist entirely of such acompound, or may further comprise one or more additional moieties,provided that the modulating activity of the active compound is notsubstantially diminished (i.e., the ability to increase or decrease MCHbinding to MCH receptor, as determined using a binding assay providedherein, is not diminished by more than 50%). Such additional moietiesinclude, for example, targeting moieties, other active agents andcarriers, any of which may be linked to the active compound via avariety of standard techniques including direct condensation, or by wayof bi- or multi-functional linkers. Alternatively, such additionalmoieties may be combined with the active compound, without covalentlinking. A modulator binds “specifically” to MCH receptor if it binds toan MCH receptor (total binding minus nonspecific binding) with a Ki thatis 10-fold, preferably 100-fold, and more preferably 1000-fold, lessthan the Ki measured for modulator binding to other G protein-coupledreceptors. A modulator binds with “high affinity” if the K_(i) at an MCHreceptor is less than 1 micromolar, preferably less than 500 nanomolar,100 nanomolar or 10 nanomolar. Assays to evaluate an effect on MCHbinding to MCH receptor, as well as MCH receptor-mediated signaltransduction, may be performed using the binding and calciummobilization assays provided herein within Examples 2 and 3,respectively.

As used herein, a “substituted 1-benzyl-4-aryl piperazine or piperidineanalogue” is any compound that satisfies the structure of Formula I.

A “targeting moiety” is a substance (e.g., a compound or a cell) thatincreases the local concentration of a modulator in the vicinity of atarget site in a patient. There are a wide variety of targeting moietiesknown in the art, including antibodies and fragments thereof, receptors,ligands and other molecules that bind to cells of, or close to, a targettissue.

A “carrier,” “carrier group” or “carrier molecule” is a substance thatmay be associated with an active compound prior to administration to apatient, generally for the purpose of controlling stability orbioavailability of the compound. Carriers for use within suchformulations are generally biocompatible, and may also be biodegradable.Carriers include, for example, monovalent or multivalent molecules suchas serum albumin (e.g., human or bovine), egg albumin, peptides,polylysine and polysaccharides such as aminodextran and polyamidoamines.Carriers also include solid support materials such as beads andmicroparticles comprising, for example, polylactate polyglycolate,poly(lactide-co-glycolide), polyacrylate, latex, starch, cellulose ordextran. A carrier may bear the compounds in a variety of ways,including covalent bonding (either directly or via a linker group),noncovalent interaction or admixture.

A “linker,” as used herein, is any molecule that does not comprise acompound that detectably modulates MCH binding to an MCH receptor, andthat can be covalently linked to at least two chemical moieties. Linkersmay be used to link another moiety to a compound that modulates MCHbinding to an MCH receptor. In general, a linker is bi-functional ormulti-functional (e.g., a branched structure). Numerous linkers areknown in the art, and may be incorporated into an MCH receptor modulatorusing any appropriate method known in the art.

A moiety is “associated with” an active compound if the moiety is linkedto (covalently or noncovalently) or combined with the active compound.

A “prodrug” is a compound that may not fully satisfy the structuralrequirements of the compounds provided herein, but is modified in vivo,following administration to a patient, to produce an active compound asdescribed herein. For example, a prodrug may be an acylated derivativeof a compound as provided herein. Prodrugs include compounds whereinhydroxy, amine or sulfhydryl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino or sulfhydryl group, respectively. Examples of prodrugs include,but are not limited to, acetate, formate and benzoate derivatives ofalcohol and amine functional groups within the compounds providedherein.

A “patient” is any individual treated with a MCH receptor modulator asprovided herein. Patients include humans, as well as other animals suchas companion animals and livestock. Patients may be afflicted with acondition associated with undesirable MCH receptor activation, or may befree of such a condition (i.e., treatment may be prophylactic).

Melanin Concentrating Hormone Receptor Modulators

As noted above, the present invention provides compounds of Formula I.Preferred such compounds are melanin concentrating hormone (MCH)receptor modulators (i.e., agents that detectably modulate both MCHbinding to MCH receptor and MCH-mediated signal transduction). Suchmodulators may be specific for a particular MCH receptor (e.g., type 1or type 2), or may inhibit or enhance ligand binding to multiple MCHreceptors. MCH receptor modulators may be used to modulate MCH bindingto MCH receptors in vivo, especially in the treatment of metabolic,feeding and sexual disorders in humans, domesticated companion animalsand livestock animals. Modulators may also be used within a variety ofin vitro assays, such as assays for receptor activity, as probes fordetection and localization of MCH receptors and as standards in assaysof MCH binding and MCH-mediated signal transduction.

The MCH receptor modulators provided herein comprise active compoundsthat are multi-aryl (i.e., have a plurality of unfused or fused arylgroups), non-peptide and amino acid free, and detectably modulate thebinding of MCH to MCH receptor at nanomolar concentrations, preferablyat subnanomolar concentrations. Active compounds provided herein aregenerally substituted 1-benzyl-4-aryl piperazine or piperidineanalogues, as defined above. Preferred compounds bind specifically, andwith high affinity, to an MCH receptor. In general, compounds providedherein have a K_(i) at an MCH receptor of less than 1 micromolar.Without wishing to be bound to any particular theory, it is believedthat the interaction of the compounds provided herein with an MCHreceptor results in the MCH receptor modulating activity of thesecompounds. Active compounds include receptor agonists and antagonists.

The present invention is based, in part, on the discovery that smallmolecules having the general Formula I (as well as pharmaceuticallyacceptable salts and prodrugs thereof) modulate MCH binding to MCHreceptor.

Within Formula I, V is a bond or —(C═O)— and W is nitrogen, CH, COH orCCN. The variable “n” is 1 or 2; in other words, the heterocyclic ringcomprising W may be a 6- or 7-membered ring, with 6-membered ringsgenerally preferred.

X is selected from halogen, hydroxy, nitro, cyano, —COOH, oxo, andgroups of the formula L-M, as defined below. As noted above, anycarbocycle may be saturated, partially saturated or unsaturated, and may(but need not) be substituted with one or more (preferably from 1 to 3)substituents. Preferably, X is halogen, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy or halo(C₁-C₃)alkoxy, with halogen, methoxy andtrifluoromethyl particularly preferred.

Y and Z are each independently: (i) CH, (ii) nitrogen, or (iii) carbonjoined to R₅ to form a carbocyclic or heterocyclic ring comprising W andV having from 5 to 8 ring members. As noted above, any carbocyclic orheterocyclic ring so formed may be saturated, partially saturated orunsaturated, and is optionally substituted with one or more (preferablyfrom 1 to 3) independently selected substituents as described above. Itwill be apparent that such a carbocyclic or heterocyclic ring includes,in addition to W and V, the carbon atom linked to V and a carbon atomadjacent to W. Within certain embodiments, Y and Z are both CH. Withincertain embodiments, either Y or Z is nitrogen; preferably Y and Z arenot both nitrogen. If one of Y or Z is joined to R₅, the other of Y andZ is either CH or nitrogen.

R₁ and R₂ are each independently selected from: (a) hydrogen, halogen,hydroxy, nitro, cyano, —COOH, and oxo; and (b) groups of the formulaL-M, as defined below. Preferably, R₁ and R₂ are each independentlyselected from hydrogen, halogen, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl,(C₁-C₃)alkoxy and halo(C₁-C₃)alkoxy, with hydrogen, halogen, methyl,methoxy and di- and tri-fluoromethyl particular preferred. Withincertain preferred embodiments, one of R₁ and R₂ is hydrogen. If R₁ andR₂ are both hydrogen, then V is preferably —(C═O)—.

R₃ is: (i) selected from hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl andhalo(C₁-C₆)alkyl; or (ii) joined to one or both of R₆ and R₁₀ to form acarbocyclic or heterocyclic group having one ring or two fused rings,wherein each ring contains from 5 to 8 ring members and 0, 1 or 2heteroatoms independently chosen from oxygen, nitrogen and sulfur, andwherein each ring is optionally substituted as described above. It willbe apparent that any ring formed with R₆ includes the carbon atoms towhich R₃ and R₆ are attached, as well as the nitrogen atom linked tothese carbon atoms. Similarly, a ring formed with R₁₀ includes thecarbon atoms to which R₃ and R₁₀ are attached, as well as theintervening carbon atom. Preferred R₃ groups are hydrogen, (C₁-C₃)alkyl(e.g., methyl or ethyl), halo(C₁-C₃)alkyl (e.g., trifluoromethyl) andgroups that form a 5-membered, partially saturated ring with R₁₀ or a 5-or 6-membered saturated or partially saturated ring with R₆.

R₄ is hydrogen, (C₁-C₆)alkyl or halo(C₁-C₆)alkyl; preferably hydrogen,methyl or trifluoromethyl, with hydrogen particularly preferred.

R₅ is: (i) independently selected at each occurrence from hydrogen,halogen, hydroxy, nitro, cyano, amino, oxo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, mono- and di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl;or (ii) joined to R₆, Y or Z to form a carbocyclic or heterocyclic ringhaving from 5 to 8 ring members, optionally substituted as describedabove. For example, R₅ may be a direct bond to R₆, Y or Z, or may be anysubstituent that, when linked to R₆, Y or Z, results in a carbocyclic orheterocyclic ring of the appropriate size. As noted above, such acarbocyclic or heterocyclic ring includes W and V, as well as the carbonatom linked to V and a carbon atom adjacent to W. Preferably, each R₅ isindependently hydrogen or methyl.

R₆ is: (i) selected from hydrogen, halogen, hydroxy, nitro, cyano,amino, oxo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, mono- and di(C₁-C₆)alkylamino, andamino(C₁-C₆)alkyl; or (ii) joined with R₃ or R₅ to form a carbocyclic orheterocyclic group as described above. Preferably, R₆ is hydrogen ormethyl, or is joined with R₃ to form a saturated or partially saturated5- or 6-membered ring.

R₇ is: (a) selected from hydrogen, halogen, hydroxy, nitro, cyano,—COOH, oxo; and groups of the formula L-M, as defined below; or (b)joined with R₈ or R₁₂ to form a fused 5- or 6-membered carbocyclic orheterocyclic group (saturated, partially saturated or unsaturated, andoptionally substituted). It will be apparent that any ring formed withR₈ includes the carbon atoms to which R₇ and R₈ are attached. Similarly,a ring formed with R₁₂ includes the carbon atoms to which R₇ and R₁₂ areattached. Within certain embodiments, R₇ is preferably hydrogen.

R₈ is: (a) selected from hydrogen, halogen, hydroxy, nitro, cyano,—COOH, oxo; and groups of the formula L-M, as defined below; or (b)joined with R₇ or R₁₁ to form a fused 5- to 10-member carbocyclic orheterocyclic group. Preferably, R₈ is hydrogen, halogen, (C₁-C₃)alkyl,halo(C₁-C₃)alkyl, (C₁-C₃)alkoxy or halo(C₁-C₃)alkoxy, or R₈ is joinedwith R₇ or R₁₁ to form a fused 5- or 6-membered ring, or a fused 9- or10-membered bicyclic group.

U is N, O or CR₉; and R₉ is (a) selected from hydrogen, halogen,hydroxy, nitro, cyano, COOH, oxo, and groups of the formula L-M, asdefined below; or (b) joined with R₁₀ or R₁₁ to form a fused 5- to10-member carbocyclic or heterocyclic group. It will be apparent thatany ring formed with R₁₀ includes the carbon atoms to which R=and R₁₀are attached. Similarly, a ring formed with R₁₁ includes the carbonatoms to which R₉ and R₁₁ are attached. Preferably, R₉ is hydrogen,halogen, (C₁-C₃)alkyl (e.g., methyl) or (C₁-C₃)alkoxy (e.g., methoxy),or is fused with R₁₀ or R₁₁ to form a 6-membered aromatic ring.

T is N, O or CR₁₀; and R₁₀ is: (a) selected from hydrogen, halogen,hydroxy, nitro, cyano, —COOH, oxo, and groups of the formula L-M, asdefined below; or (b) joined with R₃, R₈ or R₉ to form a carbocyclic orheterocyclic group as described above.

R₁₁ is: (a) selected from hydrogen, halogen, hydroxy, nitro, cyano,—COOH, oxo, and groups of the formula L-M, as defined below; or (b)joined with one or both of R₈ and R₉ to form a fused 5- to 10-membercarbocyclic or heterocyclic group; Preferably, R₁₁ is hydrogen, hydroxy,halogen, (C₁-C₃)alkyl, halo(C₁-C₃)alkyl (e.g., trifluoromethyl) or(C₁-C₃)alkoxy (e.g., methoxy or ethoxy).

R₁₂ is: (i) independently selected at each occurrence from hydrogen,halogen, hydroxy, nitro, cyano, amino, oxo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, mono- and di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl;or (ii) joined to R₇ to form a fused carbocyclic or heterocyclic ring asdescribed above. Preferably R₁₂ is hydrogen or methyl.

L is independently at each occurrence a bond, —NR₁₁— —O—, —SO₂—,—SO₂NH—, C(═O)NR₁₁— or NR₁₁C(═O)—, wherein R₁₁ is independently selectedat each occurrence from hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl and halo(C₁-C₆)alkyl.

M is independently at each occurrence a hydrogen, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halo(C₁-C₆)alkyl, amino(C₁-C₆ alkyl) ora 5- to 10-membered carbocycle.

Within certain preferred embodiments, at least one of R₁₀, R₃ and R₄ isnot hydrogen. In particular, R₁₀, R₃ and R₄ are preferably not allhydrogen if R₁₁ is halogen and V is a bond.

Within certain embodiments, preferred compounds are chiral, and satisfyFormula Ia:

Within Formula Ia, one or both of R₃ and R₁₂ is not hydrogen. Variablesshown in Formula Ia are otherwise as defined for Formula I. If R₃ is nothydrogen, then the carbon to which R₃ is attached is in the Rconfiguration (assuming that R₃ has a lower priority than the othergroups attached to the carbon); in other words, for compounds having analpha-methyl or -ethyl benzyl group (R₃ is methyl or ethyl, R₄ ishydrogen), the R enantiomer is generally preferred. Similarly if R₁₂ isnot hydrogen, then the carbon to which R₁₂ is attached is in the Sconfiguration (if R₁₂ has a lower priority than the other groupsattached to the carbon). Compounds with chiral carbon atoms may beindicated as the R or S enantiomers; compounds in which neither R₃ norR₁₂ is hydrogen may be indicated herein as the (R,S) enantiomer. In theabsence of such designation, compounds specifically recited hereinshould be interpreted as encompassing both racemic and chiral forms. Inaddition, solid black lines of constant width are used within certainstructures provided herein to indicate relative stereochemistry of onestereocenter with respect to another. Such lines do not indicateabsolute stereochemistry (which is indicated herein using standard wedgelines).

Certain compounds provided herein satisfy one or more of Formulas II-IV,in which variable positions are defined as in Formula I:

Within Formula II, R₃ and R₆ are joined to form an unsaturated,partially unsaturated or saturated ring, wherein the ring contains 5 to8 ring members of which 0, 1 or 2 are heteroatoms (independently chosenfrom oxygen, nitrogen and sulfur). Similarly, within Formula III, R₃ andR₁₀ are joined to form an unsaturated, partially unsaturated orsaturated ring that contains 5 to 8 ring members of which 0, 1 or 2 areheteroatoms. Within Formula IV, R₃, R₆ and R₁₀ are joined to form twofused rings, each of which is independently unsaturated, partiallysaturated or saturated, and each of which contains from 5 to 8 ringmembers of which 0, 1 or 2 are heteroatoms.

A representative example of Formula II is shown below:

Within Formula Ia, A and B are each independently selected from O, N, S,CR₁₃ and CHR₁₃, wherein R₁₃ is independently selected at each occurrencefrom hydrogen, halogen, cyano, hydroxy, oxo, oxime, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, C₁-C₆ alkoxycarbonyl,halo(C₁-C₆)alkyl and halo(C₁-C₆)alkoxy. Preferably, R₄ is hydrogen ormethyl, R₅ is independently selected at each occurrence from hydrogenand methyl, R₁₁ is hydrogen, halogen, methoxy or hydroxy and R₇, R₈ andR₉ are each independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkoxy and halogen.

Representative compounds of Formula I include, but are not limited tothose in which W is N and R₃ and R₄ are both H. Such compounds include,for example:1-(4-bromo-3-methoxyphenyl)-4-(3,4-dimethoxybenzyl)piperazine;1-(4-bromo-3-methoxy-phenyl)-4-(4-chlorobenzyl)piperazine;1-[4-chloro-3-(trifluoromethyl)phenyl]-4-(3,4-dimethoxybenzyl)piperazine;1-(3,4-dichlorophenyl)-4-(3,4-dimethoxybenzyl)piperazine;1-(4-bromo-3-methoxyphenyl)-4-(4-methoxy-2,5-dimethylbenzyl)piperazine;1-(4-bromo-3-methoxyphenyl)-4-(4-methoxy-2,3-dimethylbenzyl)piperazine;1-(3-bromo-4-methoxybenzyl)-4-(4-bromo-3-methoxyphenyl)piperazine;4-{[4-(4-bromo-3-methoxy-phenyl)piperazin-1-yl]methyl}-2-methoxyphenol;4-({4-[4-chloro-3-(trifluoromethyl)phenyl]-piperazin-1-yl}methyl)-2-methoxyphenol;1-[4-chloro-3-(trifluoromethyl)phenyl]-4-(4-methoxy-2,3-dimethylbenzyl)piperazine;1-(3-bromo-4-methoxybenzyl)-4-[4-chloro-3-(trifluoromethyl)phenyl]piperazine;1-(4-bromo-3-methoxyphenyl)-4-(4-methoxy-3-methylbenzyl)piperazine;1-[4-chloro-3-(trifluoromethyl)phenyl]-4-(4-methoxy-3-methylbenzyl)piperazine;1-(4-chloro-3-trifluoromethoxyphenyl)-4-[1-(3,4-dimethoxy-benzyl)]-2-methyl-piperazine;4-(4-chloro-3-trifluoromethyl-phenyl)-[1-(3,4-dimethoxy-benzyl)-2-methyl-piperazine;4-(4-chloro-3-methoxy-phenyl)-1-(3,4-dimethoxy-benzyl)-2-methylpiperazine;4-(4-chloro-3-methoxy-phenyl)-[1-(3,4-dimethoxy-benzyl)-ethyl]-2-methylpiperazine;3-{[4-(4-bromo-3-methoxyphenyl)piperazin-1-yl]methyl}-9-ethyl-9H-carbazole;1-(5-bromo-6-methoxypyridin-2-yl)-4-(3,4-dimethoxybenzyl)piperazine;1-(5-bromo-6-methoxypyridin-2-yl)-4-(4-chlorobenzyl)piperazine;1-(5-bromo-6-methoxypyridin-2-yl)-4-(4-methoxy-2,5-dimethylbenzyl)piperazine;1-(5-bromo-6-methoxypyridin-2-yl)-4-(4-methoxy-2,3-dimethylbenzyl)piperazine;1-(3-bromo-4-methoxybenzyl)-4-(5-bromo-6-methoxypyridin-2-yl)piperazine;4-(5-bromo-6-methoxypyridin-2-yl)-1-(3,4-dimethoxybenzyl)-2-methylpiperazine;4-(5-bromo-6-methoxypyridin-2-yl)-1-(3,4-dimethoxy-benzyl)-2-methylpiperazine;1-(5-bromo-6-methoxypyridin-2-yl)-4-(4-methoxy-3-methylbenzyl)piperazine;3-{[4-(5-bromo-6-methoxypyridin-2-yl)piperazin-1-yl]methyl}-9-ethyl-9H-carbazole;4-{[4-(5-bromo-6-methoxypyridin-2-yl)piperazin-1-yl]methyl}-2-methoxyphenol;and 1-(4-bromo-3-methoxyphenyl)-4-(3,4-dimethoxybenzyl)-1,4-diazepane.

Within other embodiments, W is N and R₃ is not hydrogen. Such compoundsinclude, for example:1-(4-bromo-3-methoxyphenyl)-4-[1-(3,4-dimethoxyphenyl)-ethyl]piperazine;1-[4-chloro-3-(trifluoromethyl)phenyl]-4-[1-(3,4-dimethoxyphenyl)ethyl]-piperazine;1-(4-bromo-3-methoxyphenyl)-4-[1-(4-methoxyphenyl)ethyl]piperazine;1-(4-chloro-3-methoxyphenyl)-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine;1-(4-bromo-3-methoxyphenyl)-4-[1-(3,4-difluorophenyl)ethyl]piperazine;4-{1-[4-(4-bromo-3-methoxyphenyl)piperazin-1-yl]ethyl}-2-methylphenol;1-(4-bromo-3-methoxyphenyl)-4-[1-(4-fluoro-3-methoxyphenyl)-ethyl]piperazine;1-(4-chloro-3-methoxyphenyl)-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine;1-(4-chloro-3-methoxyphenyl)-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine;1-(4-bromo-3-trifluoromethoxyphenyl)-4-[1-(3-fluoro-4-methoxyphenyl)ethyl]piperazine;1-(4-bromo-3-trifluoromethoxyphenyl)-4-[1-(3-fluoro-4-methoxyphenyl)ethyl]piperazine;1-(4-bromo-3-trifluoromethylphenyl)-4-[1-(3-fluoro-4-methoxyphenyl)ethyl]piperazine;1-(4-methoxy-phenyl)-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine;1-(4-methoxy]phenyl)-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine;1-(4-bromo-3-methoxy-phenyl)-4-[1-(4-chloro-phenyl)ethyl]-piperazine;1-(4-chloro-3-methoxy-phenyl)-4-[1-(4-methoxy-2,3-dimethyl-phenyl)ethyl]-piperazine;1-(4-chloro-3-methoxy-phenyl)-4-[1-(4-chloro-3-methoxy-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxy-phenyl)-4-[1-(4-methoxy-2,5-dimethyl-phenyl)-ethyl]-piperazine;1-(4-fluoro-3-trifluoromethyl-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxy-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine;1-(4-chloro-3-trifluoromethyl-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxy-phenyl)-4-[1-(4-ethoxy-3-methoxy-phenyl)-ethyl]-piperazine;1-(4-chloro-3-methoxy-phenyl)-4-[1-(4-fluoro-3-methoxy-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxy-phenyl)-4-[1-(2,4,5-trimethyl-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxyphenyl)-4-[1-(3-fluoro-4-methoxy-phenyl)-ethyl]-piperazine;1-(4-chloro-3-trifluoromethylphenyl)-4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine;1-(4-fluoro-3-methoxyphenyl)-4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine;1-(4-chloro-3-trifluoromethylphenyl)-4-[1-(4-chloro-3-methoxy-phenyl)-ethyl]-piperazine;1-(4-chloro-3-trifluoromethylphenyl)-4-[1-(4-methoxy-3-methyl-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxyphenyl)-4-[1-(3-methoxy-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxy-phenyl)-4-[1-(4-trifluoromethyl-phenyl)-ethyl]-piperazine;4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine;1-(4-chloro-3-methoxy-phenyl)-4-[1-(3-fluoro-4-methoxy-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxy-phenyl)-4-[1-(3-ethoxy-phenyl)ethyl]-piperazine;1-(5-{1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethyl}-2-fluoro-phenyl)-ethanone;1-(4-chloro-3-methyl-phenyl)-4-[1-(4-methoxy-3-methyl-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxy-phenyl)-4-[1-(3,5-dimethoxy-phenyl)-ethyl]-piperazine;1-(4-methoxy-3-methyl-phenyl)-4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine;1-(4-chloro-3-methyl-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxy-phenyl)-4-[1-(3,4-diethoxy-phenyl)-ethyl]-piperazine;1-(4-chloro-3-fluoro-phenyl)-4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine;1-(4-chloro-3-methyl-phenyl)-4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine;1-(4-chloro-3-fluoro-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine;1-(4-methoxy-3-methyl-phenyl)-4-[1-(3-methyl-4-methoxy-phenyl)-ethyl]-piperazine;1-(4-methoxy-3-methyl-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine;1-(3,4-dimethoxy-phenyl)-4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine;1-(4-fluoro-3-trifluoromethyl-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxy-phenyl)-4-{1-[4-(4-bromo-phenyl)-phenyl]-ethyl}-piperazine;4-(4-chloro-3-trifluoromethyl-phenyl)-[1-(3,4-dimethoxy-benzyl)-ethyl]-piperazine;1-(1-benzo[1,3]dioxol-5-yl-ethyl)-4-(4-bromo-3-methoxy-phenyl)-piperazine;1-(4-bromo-3-methoxy-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-ethyl]-[1,4]diazepane;1-(4-bromo-3-methoxy-phenyl)-4-[1-(3-fluoro-4-methoxy-phenyl)-ethyl]-[1,4]diazepane;1-[1-(3,4-dimethoxy-phenyl)-ethyl]-4-(3-methoxy-phenyl)-piperazine-2,5-dione;1-(4-bromo-3-methoxy-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-propyl]-piperazine;1-(4-chloro-3-trifluoromethyl-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-propyl]-piperazine;1-(5-bromo-6-methoxypyridin-2-yl)-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine;1-(5-bromo-6-methoxy-pyridin-2-yl)-4-[1-(4-trifluoromethyl-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxy-phenyl)-4-[1-(6-methoxy-naphthalen-2-yl)-ethyl]-piperazine;1-(4-chloro-3-methoxy-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine;1-(4-bromo-3-methoxy-phenyl)-4-[1-(4-fluoro-3-methoxy-phenyl)-ethyl]-piperazine;and1-(4-bromo-3-methoxy-phenyl)-4-[1-(6-methoxy-pyridin-2-yl)-ethyl]-piperazine.

Representative compounds in which W is C, COH or CCN include, forexample:4-(4-chloro-3-trifluoromethyl-phenyl)-1-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperidine;and4-[4-chloro-3-(trifluoromethyl)phenyl]-1-(3,4-dimethoxybenzyl)piperidin-4-ol.

Representative compounds of Formula II include, for example:2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-trifluoromethyl-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-methoxy-phenyl)-6-(3-fluoro,4-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-fluoro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[t1,2-a]pyrazine;2-(4-fluoro-3-trifluoromethyl-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-methoxy-phenyl)-6-methoxy-naphthalen-2-yl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-methyl-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-methoxy-3-methyl-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-methoxy-phenyl)-6-(3-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(2,4-dibromo-5-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(3,4-dimethoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-fluoro-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;1-(4-fluoro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-ol;2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one;2-(4-chloro-3-methoxy-phenyl)-6-(3-fluoro-4-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one;2-(4-chloro-3-methoxy-phenyl)-6-(6-methoxy-naphthalen-2-yl)-octahydro-pyrido[1,2-a]pyrazin-8-one;8-(4-chloro-3-methoxy-phenyl)-4-(3,4-dimethoxy-phenyl)-octahydro-pyrazino[2,1-c][1,4]thiazine;2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrrolo[1,2-a]pyrazine;2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-1,3,4,6,9,9a-hexahydro-2H-pyrido[1,2-a]pyrazine;8-bromo-3-(3,4-dimethoxy-benzyl)-9-methoxy-2,3,4,4a-tetrahydro-1H,6H-pyrazino[1,2-a]quinoxalin-5-one;7-(4-chloro-3-methoxy-phenyl)-4-(3,4-dimethoxy-phenyl)-decahydro-naphthalen-2-ol;and2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-8-fluoro-octahydro-pyrido[1,2-a]pyrazine.

Representative compounds of Formula II include, for example:1-(4-bromo-3-methoxyphenyl)-4-(5,6-dimethoxy-2,3-dihydro-s1-indan-1-yl)piperazine;1-(5-bromo-6-methoxypyridin-2-yl)-4-(5,6-dimethoxy-2,3-dihydro-1H-indan-1-yl)piperazine;1-(4-chloro-3-trifluoromethyl-phenyl)-4-(4,5-dimethoxy-indan-1-yl)-piperazine;and1-(4-bromo-3-methoxy-phenyl)-4-(4,5-dimethoxy-indan-1-yl)-piperazine.

Representative compounds in which V is —C(═O)— include, for example:(4-chloro-phenyl)-{4-[1-(2,3-dimethyl-phenyl)-ethyl]-piperazin-1-yl}-methanone;(4-chloro-phenyl)-{4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazin-1-yl}-methanone;(4-trifluoro-methyl-phenyl)-{4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazin-1-yl}-methanone;(3,4-dichloro-phenyl)-{4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazin-1-yl}-methanone;(4-chloro-phenyl)-{4-[1-(4-methyl-naphthalen-1-yl)-ethyl]-piperazin-1-yl}-methanone;(4-trifluoro-methyl-phenyl)-{4-[1-(4-methoxy-2-methyl-phenyl)-ethyl]-piperazin-1-yl}-methanone;(4-trifluoromethyl-phenyl)-{4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazin-1-yl}-methanone;4-trifluoromethyl-phenyl)-{4-[1-(4-methoxy-3-methyl-phenyl)-ethyl]-piperazin-1-yl}-methanone;(4-chloro-phenyl)-{4-[1-(4-methoxy-naphthalen-1-yl)-ethyl]-piperazin-1-yl}-methanone;4-trifluoromethyl-phenyl)-{4-[1-(4-methoxy-2,3-dimethyl-phenyl)-propyl]-piperazin-1-yl}-methanone;(4-chloro-phenyl)-{4-[1-(4-methoxy-2,3-dimethyl-phenyl)-allyl]-piperazin-1-yl}-methanone;4-fluoro-phenyl)-{4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazin-1-yl}-methanone;4-bromo-3-methyl-phenyl)-{4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazin-1-yl}-methanone;(3,4-dichloro-phenyl)-{4-[1-(4-methyl-naphthalen-1-yl)-ethyl]-piperazin-1-yl}-methanone;[6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-(4-trifluoromethyl-phenyl)-methanone;4-chloro-phenyl)-{4-[1-(4-methoxy-2,3-dimethyl-phenyl)-propyl]-piperazin-1-yl}-methanone;{4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-[1,4]diazepan-1-yl}-(4-trifluoromethyl-phenyl)-methanone;and{5-[1-4-methoxy-2,3-dimethyl-phenyl)-ethyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-(4-trifluoromethyl-phenyl)-methanone.

Representative compounds in which U is nitrogen or oxygen include, forexample:3-{1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethyl}-6-methoxy-quinoline;3-{1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethyl}-2-chloro-6-methoxy-quinoline;3-t 1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethyl}-quinoline;1-(4-bromo-3-methoxy-phenyl)-4-[1-(6-methoxy-pyridin-3-yl)-ethyl]-piperazine;and3-{1-[4-(4-Bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethyl}-6-fluoro-4-methyl-2H-chromen-2-ol.

Representative chiral compounds provided herein include, for example,(3S)-1-(4-chloro-3-trifluoromethoxyphenyl)-4-[1-(3,4-dimethoxy-benzyl)]-2-methyl-piperazine;(2S)-4-(5-bromo-6-methoxypyridin-2-yl)-1-(3,4-dimethoxy-benzyl)-2-methylpiperazine;R-1-(4-chloro-3-methoxyphenyl)-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine;S-1-(4-chloro-3-methoxyphenyl)-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine;R-1-(4-bromo-3-trifluoromethoxyphenyl)-4-[1-(3-fluoro-4-methoxyphenyl)ethyl]piperazine;S-1-(4-bromo-3-trifluoromethylphenyl)-4-[1-(3-fluoro-4-methoxyphenyl)ethyl]piperazine;S-1-(4-methoxy-phenyl)-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine;R-1-(4-methoxy]phenyl)-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine;R-1-(4-chloro-3-methoxy-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine;{5-[1-4-methoxy-2,3-dimethyl-phenyl)-ethyl]-(1S,4S)-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-(4-trifluoromethyl-phenyl)-methanone;(6R,10S)-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one;R-1-(4-bromo-3-methoxyphenyl)-4-[1-(3,4-dimethoxyphenyl)-ethyl]piperazine;(2S)-4-(4-chloro-3-methoxyphenyl)-1-(3,4-dimethoxybenzyl)-2-methyl-piperazine;(2R)-4-(4-chloro-3-methoxyphenyl)-1-(3,4-dimethoxybenzyl)-2-methyl-piperazine;(3R)-1-(4-fluoro-3-trifluoromethyl-phenyl)-4-[1-(3,4-dimethoxyphenyl)-ethyl]-piperazine;(3S)-1-(4-fluoro-3-trifluoromethyl-phenyl)-4-[1-(3,4-dimethoxyphenyl)-ethyl]-piperazine;(3R)-1-(4-chloro-3-trifluoromethyl-phenyl)-4-[1-(3,4-dimethoxyphenyl)-ethyl]-piperazine;(3S)-1-(4-chloro-3-trifluoromethyl-phenyl)-4-[1-(3,4-dimethoxyphenyl)-ethyl]-piperazine;(6R,10S)-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;(3R)-1-(4-fluoro-3-methoxy-phenyl)-4-[1-(3,4-dimethoxyphenyl)-ethyl]-piperazine;(2R)-4-(4-chloro-3-trifluoromethylphenyl)-[1-(3,4-dimethoxybenzyl)-ethyl]-piperazine;(6R,9S)-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrrolo[1,2-a]pyrazine;(6R,10S)-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-ol;(6R,10S)-[6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-(4-trifluoromethyl-phenyl)-methanone;(6R,10S)-2-(4-chloro-3-methoxy-phenyl)-6-(3-fluoro,4-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine; and{5-[1-4-methoxy-2,3-dimethyl-phenyl)-ethyl]-(1S,4S)-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-(4-trifluoromethyl-phenyl)-methanone.

It will be apparent that the specific compounds recited above areillustrative examples of compounds provided herein, and are not intendedto limit the scope of the present invention. As noted above, allcompounds of the present invention may be present as a free base or as apharmaceutically acceptable acid addition salt. In addition, wherechirality is not specified, both chiral compounds and racemic mixturesare encompassed by the present invention, although chiral forms asdescribed above may be preferred.

Substituted 1-benzyl-4-aryl piperazine and piperidine analogues providedherein detectably alter (modulate) MCH binding to MCHR1 and/or MCHR2receptor, as determined using a standard in vitro MCH receptor bindingassay and/or calcium mobilization assay. References herein to a “MCHreceptor ligand binding assay” are intended to refer to the standard invitro receptor binding assay provided in Example 2. Briefly, acompetition assay may be performed in which an MCH receptor preparationis incubated with labeled (e.g., ¹²⁵I) MCH and unlabeled test compound.Within the assays provided herein, the MCH receptor used is preferably amammalian MCHR1 or MCHR2 receptor, more preferably a human or monkeyMCHR1 or MCHR2 receptor. The receptor may be recombinantly expressed ornaturally expressed, and may comprise a native sequence or a modifiedsequence (e.g., truncated and/or fused to a non-native N-terminalsequence). The MCH receptor preparation may be, for example, a membranepreparation from HEK293 cells that recombinantly express a human MCHreceptor (e.g., Genbank Accession No. Z86090), monkey MCHR1 receptor(such as the MCHR1 sequence provided in SEQ ID NO:1), or humanMCHR1/human beta-2-adrenergic chimeric receptor.

Incubation with a compound that detectably modulates MCH binding to MCHreceptor will result in a decrease or increase in the amount of labelbound to the MCH receptor preparation, relative to the amount of labelbound in the absence of the compound. Preferably, such a compound willexhibit a K_(i) at an MCH receptor of less than 1 micromolar, morepreferably less than 500 nM, 100 nM, 20 nM or 10 nM, within a MCHreceptor ligand binding assay performed as described in Example 2.Generally preferred compounds are MCH receptor antagonists, and exhibitEC₅₀ values of about 4 micromolar or less, more preferably 1 micromolaror less, still more preferably about 100 nanomolar or less, 10 nanomolaror less or 1 nanomolar or less within a standard in vitro MCH receptormediated calcium mobilization assay, as provided in Example 3.

If desired, compounds of the present invention may be evaluated forcertain pharmacological properties including, but not limited to, oralbioavailability, toxicity, serum protein binding and in vitro and invivo half-life. In addition, penetration of the blood brain barrier maybe desirable for compounds used to treat CNS disorders, while low brainlevels of compounds used to treat peripheral disorders may be preferred.Routine assays that are well known in the art may be used to assessthese properties, and identify superior compounds for a particular use.For example, assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity may be assessed using any standard method, such asthe assay detecting an effect on cellular ATP production provided inExample 5. Penetration of the blood brain barrier of a compound inhumans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously. Serum proteinbinding may be predicted from albumin binding assays. Such assays aredescribed in a review by Oravcová, et al. (Journal of Chromatography B(1996) volume 677, pages 1-27). Compound half-life is inverselyproportional to the frequency of dosage of a compound. In vitrohalf-lives of compounds may be predicted from assays of microsomalhalf-life as described by Kuhnz and Gieschen (Drug Metabolism andDisposition, (1998) volume 26, pages 1120-1127).

In general, preferred compounds of the present invention do notsubstantially interact with dopamine receptors, particularly humandopamine D2 and D4 receptors. Dopamine receptor binding assays may bepreformed using standard methods, such as the assay described in Example4. Preferably, compounds exhibit K_(i) values greater than 1 micromolarwithin such an assay.

As noted above, MCH receptor modulators provided herein may comprise, inaddition to an active compound of Formula I, one or more additionalassociated moieties. Such moieties may be linked directly (i.e., via abond) or by way of a linker, may be noncovalently linked or may becombined with the compound. Such additional moieties may be used, forexample, to facilitate delivery, targeting or detection of the compound.Such moieties may be linked directly (i.e., via a bond) or by way of alinker. For example, while compounds described above may sufficientlytarget a desired site in vivo, it may be beneficial for certainapplications to include an additional targeting moiety to facilitatetargeting to one or more specific tissues. Preferred targeting moietiesinclude, for example, those that target specifically to brain regionsassociated with MCH activity.

For certain embodiments, it may be beneficial to also, or alternatively,associate a drug with a modulator. As used herein, the term “drug”refers to any bioactive agent intended for administration to a mammal toprevent or treat a disease or other undesirable condition. Drugs includehormones, growth factors, proteins, peptides and other compounds. Forexample, modulators for treatment of obesity may comprise leptin, aleptin receptor agonist, a melanocortin receptor 4 (MC4) agonist,sibutramine, dexenfluramine, a growth hormone secretagogue, a beta-3agonist, a 5HT-2 agonist, an orexin antagonist, a neuropeptide Y₁ or Y₅antagonist, a galanin antagonist, a CCK agonist, a GLP-1 agonist and/ora corticotropin-releasing hormone agonist. Moieties that facilitatedetection include radionuclides, luminescent groups, fluorescent groupsand enzymes, any of which may be linked to a compound via standardmethods.

For detection purposes, as discussed in more detail below, compoundsprovided herein may be isotopically-labeled or radiolabeled. Suchcompounds are identical to those recited in Formulas I, but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number most commonlyfound in nature. Examples of isotopes that can be incorporated intocompounds provided herein include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl. In addition,substitution with heavy isotopes such as deuterium (i.e., ²H) can affordcertain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.

Other moieties that may be associated with an active compound includecarriers. Such substances may modulate bioavailability or stability ofthe compound. Representative carriers include, for example, moleculessuch as albumin, polylysine, polyamidoamines, peptides, proteins,polystyrene, polyacrylamide, lipids, ceramide and biotin, solid supportmaterials such as beads and microparticles comprising, for example,polylactate, polyglycolate, poly(lactide-co-glycolide), polyacrylate,latex, starch, cellulose or dextran.

Preparation of MCH Receptor Modulators

Compounds provided herein may generally be prepared using standardsynthetic methods. Starting materials are generally readily availablefrom commercial sources, such as Sigma-Aldrich Corp. (St. Louis, Mo.).For example, a synthetic route similar to that shown in any one ofSchemes A to K may be used. It will be apparent that the final product,and any intermediate(s) shown in the following schemes may be extracted,dried, filtered and/or concentrated, and may be further purified (e.g.,by chromatography). Further experimental details for synthesis ofrepresentative compounds via these schemes are provided in Example 1,herein.

Briefly, one equivalent each of substituted piperazine and benzaldehydeare reacted with an excess of NaBH(OAc)₃ under a nitrogen atmosphereuntil no starting material is detectable by TLC. At that time, thereaction is quenched with saturated aqueous NaHCO₃ and extracted withethyl acetate to yield the 1-benzyl-4-aryl piperazine analogue. Extractsmay be dried over anhydrous MgSO₄, concentrated in vacuo andchromatographed.

Briefly, one equivalent each of substituted piperazine and acetophenoneare heated with Ti(OiPr)₄ (e.g., 70° C. for 2 hours). The reactionsolution is cooled and reacted with NaBH₄ to yield the 1-benzyl-4-arylpiperazine analogue. The reaction is quenched by the addition of 1 NNaOH and may be extracted with CH₂Cl₂. CH₂Cl₂ extracts may be dried overanhydrous MgSO₄, concentrated in vacuo, and subjected to chromatography.

Briefly, a solution containing an aromatic carboxaldehyde, benzotriazoleand an aromatic piperazine in ethanol/toluene is heated and the solutionis concentrated. Residue is coevaporated with toluene, then dissolved inTHF and treated with methyl magnesium bromide in diethyl ether to yieldthe 1-benzyl-4-aryl piperazine analogue.

2. Buchwald Coupling

Briefly, di-t-butyl dicarbonate is reacted with L-2-amino-pent-4-enoicacid in 1N NaOH and dioxane, and then concentrated (step 1). The aqueousresidue is chilled on ice, layered with EtOAc and acidified. In step 2,the reaction product, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCI), and an aniline are combined in pyridine. In step3, alane-N,N-dimethylethylamine complex in toluene is added.Chloroacetylchloride is added in step 4, and the layers are separated.In step 5, trifluoroacetic acid is added, andalane-N,N-dimethylethylamine complex in toluene is added in step 6. Instep 7, the reaction product is reacted with di-t-butyldicarbonate.Palladium (II) chloride and copper (I) chloride are added in step 8, andoxygen gas is bubbled into the solution. In step 9, trifluoroacetic acidis added, and the reaction stirred on ice and then concentrated. To thissolution is added a benzaldehyde derivative and NaOH.p-toluenesulfonylhydrazide, followed by sodium borohydride (step 10) isthen added. It will be apparent that extraction, drying, filtration,concentration, and purification steps may be needed at various points inthis scheme, as illustrated in Example 1, subpart V.

Briefly, 2-(4-benzyl-piperazin-2-yl)-ethanol is initially reacted withdi-tert-butyl dicarbonate (BOC anhydride) to yield4-benzyl-2-(2-hydroxy-ethyl)-piperazine-1-5 carboxylic acid tert-butylester (I). In step 1, I is dissolved in anhydrous dichloromethanecontaining previously activated 4 Å molecular sieves and4-methylmorpholine N-oxide. The reaction is started by addition oftetrapropylammonium perruthenate and allowed to proceed until LC/MSanalysis shows no detectable remaining starting material (typicallyabout 1 hour). The suspension is filtered and4-benzyl-2-(2-oxo-ethyl)-piperazine-1-carboxylic acid tert-butyl ester(II) is eluted with 5% methanol in chloroform. In step 2, II isdissolved in anhydrous tetrahydrofuran under nitrogen, and methylmagnesium bromide is added to yield4-benzyl-2-(2-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butylester (III). In step 3, III is treated as described above for I,yielding 4-benzyl-2-(2-oxo-propyl)-piperazine-1-carboxylic acidtert-butyl ester (IV). In step 4, trifluoroacetic acid is added to IV indichloromethane. Subsequent reaction with a benzaldehyde derivative(ArCHO) and NaOH yields compound V. In step 5, compound V is reactedwith p-toluenesulfonylhydrazide in methanol. Sodium borohydride is addedand the reaction incubated until completion, as determined by TLCanalysis (e.g., about 18 hours) to yield compound VI. In step 6,compound VI is heated with 10% Pd/C and ammonium formate (e.g., underreflux for 6 hours). Additional ammonium formate may be added, and thereaction stirred under reflux (e.g., for a further 15 hours) to affordcompound VII. Compound VII may then be dissolved in dichloromethane andstirred with triethylamine and trifluoromethylbenzoylchloride at roomtemperature (step 7a). Extraction with ethyl acetate affords compoundVIII, which may be purified on 250 micron analytical TLC. Alternatively(step 7b), compound VII may be used to generate compound IX.

Briefly, 2-tert-butoxycarbonylamino-3-mercapto-propionic acid methylester is treated with potassium hydroxide in methanol. To the reaction,a solution of 2-chloro-aryl-ethanone is added. Trifluoroacetic acid isthen added, followed by sodium triacetoxyborohydride, to yield thethiomorpholine. Reaction with trimethylaluminum and an aniline producesthe amide, which is reduced using alane. Treatment with dibromoethaneand triethylamine yields the octahydro-pyrazino thiazine derivative.

Briefly, 5-Bromo-picolinic acid is reacted with thionyl chloride,followed by hydroxyl ethylamine to yield the amide. The amide is thenreacted with an aryl boronic acid andtris(dibenzylideneacetone)-dipalladium(0) until TLC shows no detectablestarting material. Treatment with platinum dioxide results in thepiperidine compound, which is reduced using LiAlH₄. Ring formation isachieved using triphenyl phosphine and diethyl azodicarboxylate untilthere is no detectable starting material shown on TLC. Finally, an arylsubstituent is added by reaction with a bromo-aryl compound.

Briefly, reduction of ketone A to secondary alcohol B can beaccomplished by a variety of methods known to those skilled in the art,which include (but are not limited to) reaction with sodium borohydridein methanol, as described in Example 1. Fluorination of secondaryalcohols B to the secondary alkyl fluorides C can be accomplished by avariety of methods known to those skilled in the art, such as reactionwith diethylaminosulfurtrifluoride (DAST, Hudlicky, Org. React. 1988,35, 513) in solvents such as dichloromethane or chloroform, attemperatures between −78° C. and 120° C. Dehydration of a secondaryalcohol B to the corresponding olefin D can be carried out by a varietyof well-known methods, including (but not limited to) reaction withreagents such as OPCl₃ or PCl₅ in solvents such as pyridine, attemperatures between 0° C. and 200° C. Transformation of olefins D intocarbo- and heterocycles such as E can be realized by the Diels-Alderreaction, well known to those of ordinary skill in the art (e.g., L. W.Butz and A. W. Rytina, Org. React 1949, 5, 136; M. C. Kloetzel, Org.React. 1948, 4, 1). These reactions can be carried out by reacting Dwith a diene such as, but not limited to, 1,3-butadiene,2,3-dimethylbutadiene, 1,3-cyclohexadiene,1-methoxy-3-trimethylsiloxy-1,3-butadiene (“Danishefsky's diene”, S.Danishefsky and T. Kitahara, J. Am. Chem. Soc. 1974, 96, 7807),o-quinodimethane, diphenylbenzo[c]furan, or antracene.

Transformation of the ketone A into tertiary alcohols of genericstructure F can be accomplished by reaction with the appropriateorganometallic reagents such as, but not limited to, alkyl oraryllithium, alkyl or arylmagnesium halides, alkyl or arylsodium, alkylor aryl potassium, etc, in solvents such as, but not limited to,tetrahydrofuran, ethyl ether, methyl-tert-butyl ether, diisopropylether, benzene, toluene, or hexanes, at temperatures between −78° C. andthe corresponding boiling point of the reaction mixture. Directconversion of the tertiary alcohols F to the corresponding tertiaryfluorides F′ can be accomplished by a variety of methods known to thoseskilled in the art, which include but are not limited to, reaction withdiethylaminosulfurtrifluoride in solvents such as dichloromethane orchloroform, at temperatures between −78° C. and 120° C. Deoxygenation oftertiary alcohols F to the corresponding alkanes G can be carried out ina number of ways, which include treatment with triethylsilane (orequivalent hydrogen donor) in the presence of a Broensted acid (e.g.,trifluoroacetic acid) or a Lewis acid (e.g., boron trifluoride) insolvents such as dichloromethane, hexanes or ethyl ether, at reactiontemperatures in the range −78° C. to the boiling point of thecorresponding reaction mixtures. Transformation of ketone A into avariety of substituted oximes of generic structure J can be carried outby a number of methods known to those skilled in the art. These includebut are not limited to, reaction of A with hydroxylamine hydrochloride,O-methyl hydroxylamine hydrochloride, O-benzyl hydroxylaminehydrochloride, etc., in a solvent such as, but not limited to, methanol,ethanol, pyridine, N,N-dimethylformamide, dimethylsulfoxide oracetonitrile, in the presence of a base such as triethylamine, sodiumcarbonate, or sodium hydroxide, at reaction temperatures between −5° C.and the boiling point of the reaction mixture. The corresponding oxime J(R=H) can be rearranged to the lactam K or L by a variety of methodsknown to those skilled in the art (e.g., Beckmann rearrangement;Donaruma, L. G. and Heldt, W. Z. Org. React. 1960, 11, 1). Theseinclude, but are not limited to, treatment with a dehydrating agent suchas PCl₅, TsCl, sulfuric acid and the like. Lactams K and L can besubsequently reduced to the corresponding homopiperazines O and P,respectively, as those skilled in the art will recognize. Methods usedfor these transformations include, but are not limited to, treatmentwith a reducing agent such as lithium aluminum hydride, alane, borane,sodium bis(2-methoxyethoxy)aluminum hydride (Vitride, Red-Al®), in anappropriate solvent such as tetrahydrofuran, ethyl ether, toluene, etc.,at reaction temperatures between −78° C. and the boiling point of thereaction mixture (e.g., M. Hudlicky; Reductions in Organic Chemistry;Ellis Horwood Ltd.; Great Britain, 1984, pp 168.) In addition, lactams Kand L can be N-alkylated or N-arylated to the correspondingN-substituted lactams M and N, respectively. This transformation can becarried out by treatment with a strong base such as, but not limited to,sodium hydride, potassium hydride, lithium tetramethylpiperidide, orpotassium tert-butoxide, followed by treatment with an appropriatealkyl, aryl or heteroaryl halide, such as but not limited to, methyliodide, ethyl iodide, benzyl bromide, 2-fluoronitrobenzene,2-chloro-5-trifluoromethylpyridine, in the presence of a catalyst suchas, but not limited to, sodium iodide, potassium iodide ortetramethylammonium iodide, in an appropriate solvent such as, but notlimited to, tetrahydrofuran, acetonitrile, dimethylsulfoxide,N,N-dimethylformamide, tert-butanol, at reaction temperatures between−78° C. and the boiling point of the corresponding reaction mixture.

Olefination of ketone A to substituted olefins H can be realized by avariety of chemical reactions known to those skilled in the art. Amongthese are phosphorus ylides (Wittig reagents) which can be prepared bydeprotonation of phosphonium salts, which are themselves prepared by thereaction of triphenylphosphine and alkyl halides (e.g., F. A. Carey andR. J. Sundberg; Advanced Organic Chemistry, Part B, Plenum Press, NewYork, St) 1983, pp 71). Alkyl halides include, but are not limited to,methyl iodide, ethyl iodide, benzyl bromide, ethyl bromoacetate, methyl2-bromopropionate, etc. The bases needed for the deprotonation reactioninclude, but are not limited to, sodium hydroxide, sodium hydride,lithium diisopropylamide, potassium tert-butoxide, n-butyllithium andtert-butyllithium. Appropriate solvents for these reactions include, butare not limited to, water, methanol, ethanol, tetrahydrofuran,dimethylsulfoxide, benzene or ethyl ether. Reactions can be carried outat reaction temperatures between −78° C. and the boiling point of thecorresponding reaction mixture.

α-Alkylation of ketone A to mono-or polyalkylated ketone I can beaccomplished by treatment of A with a base and an alkylating agent in anappropriate solvent. Suitable bases include, but are not limited to,lithium diisopropylamide, lithium hexamethyldisilazide, potassiumtert-butoxide, sodium methoxide and lithium2,2,6,6-tetramethylpiperidide. Alkylating reagents include, but are notlimited to, methyl iodide, ethyl iodide, 2-iodopropane, methylorthoformate, benzyl bromide, and phenethyl bromide. Suitable solventsinclude, but are not limited to, tetrahydrofuran, dimethylsulfoxide,N,N-dimethylformamide, tert-butanol and methanol. Reaction temperaturesrange from −78° C. to the boiling point of the reaction mixture.

Conversion of ketone A to lactones Q and R can be accomplished by thoseskilled in the art by means of the Baeyer-Villiger reaction. Thisreaction involves the treatment of A with an oxidant such as, but notlimited to, hydrogen peroxide, peroxybenzoic acid, peroxyacetic acid orm-chloroperoxybenzoic acid in a solvent such as, but not limited to,dichloromethane, chloroform, benzene, at temperatures ranging from −30°C. to the boiling point of the reaction mixture.

Transformation of ketone A to gem-difluoride S can be accomplished, forexample, by treatment with diethylaminosulfurtrifluoride in solventssuch as dichloromethane or chloroform, at temperatures between −78° C.and 120° C.

Transformation of ketone A into nitrile T can be accomplished by avariety of methods known to those skilled in the art. One example ofsuch conditions is reaction with tosylmethylisocyanide in the presenceof a base such as, but not limited to, potassium tert-butoxide, insolvents such as 1,2-dimethoxyethane at temperatures between 10° C. andthe boiling point of the solvent (see, e.g., O. H. Oldenziel et al., J.Org. Chem. 1977, 42, 3114).

Briefly, the BOC protected 5-oxo-pyrroldine-1,2-dicarboxylatic acid (1)is converted to the benzyl ester (2) with one equivalent of benzylbromide and 2.5 equivalents of potassium carbonate. Grignard addition ofaryl magnesium bromide in THF (e.g., at 0° C. for 2 hours) followed byaqueous work-up provides the ketone,2-tert-butoxycarbonylamino-5-aryl-5-oxo-pentanoic acid benzyl ester (3).Deprotection and cyclization is conducted by treatment withtrifluoroacetic acid in dichloromethane at (e.g., at 0° C. followed byslow warming to room temperature over 2 hours). Basification with 1NNaOH to pH 7 and organic extraction provides5-aryl-3,4-dihydro-2H-pyrrole-2-carboxylic acid benzyl ester TFA salt(4). Hydrogenation at 50 psi in methanol with Pd/C catalyst (e.g., for15 hours) provides 5-aryl-pyrrolidine-2-carboxylic acid TFA salt (5).Amine protection with di-t-butyldicarbonate in dichloromethane anddiisopropylethylamaine and coupling to an aromatic amine with pyBrop anddiisopropylethylamine provides the amide, tert-butyl ester (7). Boccleavage with trifluoroacetic acid followed by alane reduction providesthe diamine (9). Alkylation with ethylbromoacetate provides theaminoester which is cyclized with sodium hydride in THF to give thelactam (11). Reduction of the lactam provides the final product (12).

Briefly, 1 equivalent each of optionally substituted benzaldehyde,piperazine-1-carboxylic acid tert-butyl ester and benzotriazole arereacted to yield the optionally substitutedphenyl-ethyl-piperazine-1-carboxylic acid tert-butyl ester. Reactionwith trifluoroacetic acid and dichloromethane results in optionallysubstituted phenyl-ethyl-piperazine. Subsequent reaction with anoptionally substituted benzoyl chloride yields the benzamide.

Briefly, reductive alkylation of 3-allyl-1-(4-aryl)-piperazine isconducted according to the procedure described in Scheme K: thepiperazine analog is heated in ethanol and toluene with one equivalentof benzotriazole and 1 equivalent of optionally substitutedbenzaldehyde. After about 20 minutes, the solution is concentrated. Theresidue is dissolved in THF and then treated with 2.5 equivalents ofvinylmagesium bromide. Following aqueous organic extraction andpurification by preparative TLC, the divinyl product is obtained. Thedivinyl compound is dissolved in dichloromethane to make a 0.05 Msolution and 0.1 equivalents of Grubb's catalyst,benzylidene-bis(tricyclohexylphosphine) dichlororuthenium, is added. Thereaction is stirred at room temperature (e.g., for 18 hours), filteredand purified by preparative TLC.

Briefly, a nitro-substituted aromatic ring linked to the piperazineester (1) to generate compound 2. Reduction of the nitro substituentyields the amine (3), which is cyclized. Addition of a second aromaticgroup results in compound 5. Optionally, additional ring substituentsmay be added (e.g., to generate compound 6). It will be apparent thatthe specific aromatic groups shown above are representative only, andare not intended to limit the scope of such groups that may be usedwithin compounds of the present invention.

In certain situations, compounds of the present invention may containone or more asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. As noted above, all stereoisomersare encompassed by the present invention. Nonetheless, it may bedesirable to obtain single enantiomers (i.e., optically active forms).Standard methods for preparing single enantiomers include asymmetricsynthesis and resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatographyusing, for example a chiral HPLC column. As noted above, for compoundshaving an alpha-methyl benzyl group (R₃ is methyl, R₄ is hydrogen) the Renantiomer is generally preferred. Asymmetric synthesis of suchcompounds may be performed using the methods illustrated in Scheme D andExample 1, herein.

As noted above, the present invention encompasses pharmaceuticallyacceptable salts of the compounds described herein. As used herein, a“pharmaceutically acceptable salt” is an acid or base salt that isgenerally considered in the art to be suitable for use in contact withthe tissues of human beings or animals without excessive toxicity,irritation, allergic response, or other problem or complication. Suchsalts include mineral and organic acid salts of basic residues such asamines, as well as alkali or organic salts of acidic residues such ascarboxylic acids. Specific pharmaceutical salts include, but are notlimited to, salts of acids such as hydrochloric, phosphoric,hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic,formic, toluenesulfonic, methanesulfonic, ethane disulfonic,2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric,tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic,succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic,phenylacetic, alkanoic such as acetic, HOOC—(CH₂)_(n)—COOH where n is0-4, and the like. Similarly, pharmaceutically acceptable cationsinclude, but are not limited to sodium, potassium, calcium, aluminum,lithium and ammonium. Those of ordinary skill in the art will recognizefurther pharmaceutically acceptable salts for the compounds providedherein, including those listed by Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).Accordingly, the present disclosure should be construed to include allpharmaceutically acceptable salts of the compounds specifically recited.

A wide variety of synthetic procedures are available for the preparationof pharmaceutically acceptable salts. In general, a pharmaceuticallyacceptable salt can be synthesized from a parent compound that containsa basic or acidic moiety by any conventional chemical method. Briefly,such salts can be prepared by reacting the free acid or base forms ofthese compounds with a stoichiometric amount of the appropriate base oracid in water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred.

Prodrugs of the compounds provided herein may be prepared by modifyingfunctional groups present in the compounds in such a way that themodifications are cleaved to the parent compounds. Prodrugs includecompounds wherein hydroxy, amine or sulfhydryl groups are bonded to anygroup that, when administered to a mammalian subject, cleaves to form afree hydroxyl, amino, or sulfhydryl group, respectively. Examples ofprodrugs include, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups within the compoundsprovided herein. Preferred prodrugs include acylated derivatives. Thoseof ordinary skill in the art will recognize various synthetic methodsthat may be employed to prepare prodrugs of the compounds providedherein.

Additional moieties may be associated with a compound using any suitableprocedure. Covalent attachment may generally be achieved using suitablefunctional groups (e.g., hydroxyl, carboxyl, sulfhydryl or amino groups)on the compound and additional moiety. For example, a nucleophilicgroup, such as an amino or sulfhydryl group, on one may be capable ofreacting with a carbonyl-containing group, such as an anhydride or anacid halide, or with an alkyl group containing a good leaving group(e.g., a halide) on the other. The use of bifunctional, multifunctionaland/or cleavable linkers may also be desirable for certain applications.Such linkers are well known in the art. Compounds associated withcarriers may be covalently linked or, preferably, such association doesnot involve covalent interaction and is achieved by mixing.

Compounds may be radiolabeled by carrying out their synthesis usingprecursors comprising at least one atom that is a radioisotope, such ascarbon (preferably ¹⁴C), hydrogen (preferably ³H), sulfur (preferably³⁵S) or iodine (preferably ¹²⁵I, Synthesis of such radiolabeledcompounds may be conveniently performed by a radioisotope supplierspecializing in custom synthesis of radiolabeled probe compounds, suchas Amersham Corporation, Arlington Heights, Ill.; Cambridge IsotopeLaboratories, Inc. Andover, Mass.; SRI International, Menlo Park,Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSynLaboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St.Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif. Tritium-labeledcompounds are also conveniently prepared catalytically viaplatinum-catalyzed exchange in tritiated acetic acid, acid-catalyzedexchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzedexchange with tritium gas. Such preparations are also convenientlycarried out as a custom radiolabeling by any of the suppliers listedabove using the compound as substrate. In addition, certain precursorsmay be subjected to tritium-halogen exchange with tritium gas, tritiumgas reduction of unsaturated bonds, or reduction using sodiumborotritide.

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositionscomprising a MCH receptor modulator as described herein, together withat least one physiologically acceptable carrier or excipient.Pharmaceutical compositions may comprise, for example, water, buffers(e.g., neutral buffered saline or phosphate buffered saline), ethanol,mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates (e.g.,glucose, mannose, sucrose or dextrans), mannitol, proteins, adjuvants,polypeptides or amino acids such as glycine, antioxidants, chelatingagents such as EDTA or glutathione and/or preservatives. Preferredpharmaceutical compositions are formulated for oral delivery to humansor other animals (e.g., companion animals such as dogs).

If desired, other active ingredients may also be included. For example,compositions intended for the treatment of eating disorders,particularly obesity and bulimia nervosa, may further comprise leptin, aleptin receptor agonist, a melanocortin receptor 4 (MC4) agonist,sibutramine, dexenfluramine, a growth hormone secretagogue, a beta-3agonist, a 5HT-2 agonist, an orexin antagonist, a neuropeptide Y, or Y₅antagonist, a galanin antagonist, a CCK agonist, a GLP-1 agonist and/ora corticotropin-releasing hormone agonist.

Pharmaceutical compositions may be formulated for any appropriate mannerof administration, including, for example, topical, oral, nasal, rectalor parenteral administration. The term parenteral as used hereinincludes subcutaneous, intradermal, intravascular (e.g., intravenous),intramuscular, spinal, intracranial, intrathecal and intraperitonealinjection, as well as any similar injection or infusion technique. Incertain embodiments, compositions in a form suitable for oral use arepreferred. Such forms include, for example, tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Within yet otherembodiments, compositions of the present invention may be formulated asa lyophilizate.

Compositions intended for oral use may further comprise one or morecomponents such as sweetening agents, flavoring agents, coloring agentsand preserving agents in order to provide appealing and palatablepreparations. Tablets contain the active ingredient in admixture withphysiologically acceptable excipients that are suitable for themanufacture of tablets. Such excipients include, for example, inertdiluents (e.g., calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate), granulating and disintegrating agents(e.g., corn starch or alginic acid), binding agents (e.g., starch,gelatin or acacia) and lubricating agents (e.g., magnesium stearate,stearic acid or talc). The tablets may be uncoated or they may be coatedby known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent(e.g., calcium carbonate, calcium phosphate or kaolin), or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium (e.g., peanut oil, liquid paraffin or olive oil).

Aqueous suspensions comprise the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents (e.g., sodium carboxymethylcellulose,methylcellulose, hydropropylmethylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing orwetting agents (e.g., naturally-occurring phosphatides such as lecithin,condensation products of an alkylene oxide with fatty acids such aspolyoxyethylene stearate, condensation products of ethylene oxide withlong chain aliphatic alcohols such as heptadecaethyleneoxycetanol,condensation products of ethylene oxide with partial esters derived fromfatty acids and a hexitol such as polyoxyethylene sorbitol monooleate,or condensation products of ethylene oxide with partial esters derivedfrom fatty acids and hexitol anhydrides such as polyethylene sorbitanmonooleate). Aqueous suspensions may also contain one or morepreservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one ormore coloring agents, one or more flavoring agents, and one or moresweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil (e.g., arachis oil, olive oil, sesame oil or coconutoil) or in a mineral oil such as liquid paraffin. The oily suspensionsmay contain a thickening agent such as beeswax, hard paraffin or cetylalcohol. Sweetening agents such as those set forth above, and/orflavoring agents may be added to provide palatable oral preparations.Such suspension may be preserved by the addition of an anti-oxidant suchas ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil (e.g., olive oil orarachis oil) or a mineral oil (e.g., liquid paraffin) or mixturesthereof. Suitable emulsifying agents may be naturally-occurring gums(e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides(e.g., soy bean, lecithin, and esters or partial esters derived fromfatty acids and hexitol), anhydrides (e.g., sorbitan monoleate) andcondensation products of partial esters derived from fatty acids andhexitol with ethylene oxide (e.g., polyoxyethylene sorbitan monoleate).The emulsions may also contain sweetening and/or flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such asglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso comprise one or more demulcents, preservatives, flavoring agentsand/or coloring agents.

A pharmaceutical composition may be prepared as a sterile injectibleaqueous or oleaginous suspension. The modulator, depending on thevehicle and concentration used, can either be suspended or dissolved inthe vehicle. Such a composition may be formulated according to the knownart using suitable dispersing, wetting agents and/or suspending agentssuch as those mentioned above. Among the acceptable vehicles andsolvents that may be employed are water, 1,3-butanediol, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils may be employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectible compositions, and adjuvants such as localanesthetics, preservatives and/or buffering agents can be dissolved inthe vehicle.

Modulators may also be prepared in the form of suppositories (e.g., forrectal administration). Such compositions can be prepared by mixing thedrug with a suitable non-irritating excipient that is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

For administration to non-human animals, the composition may also beadded to animal feed or drinking water. It may be convenient toformulate animal feed and drinking water compositions so that the animaltakes in an appropriate quantity of the composition along with its diet.It may also be convenient to present the composition as a premix foraddition to feed or drinking water.

Pharmaceutical compositions may be formulated as sustained releaseformulations (i.e., a formulation such as a capsule that effects a slowrelease of modulator following administration). Such formulations maygenerally be prepared using well known technology and administered by,for example, oral, rectal or subcutaneous implantation, or byimplantation at the desired target site. Carriers for use within suchformulations are biocompatible, and may also be biodegradable;preferably the formulation provides a relatively constant level ofmodulator release. The amount of modulator contained within a sustainedrelease formulation depends upon the site of implantation, the rate andexpected duration of release and the nature of the condition to betreated or prevented.

Modulators are generally present within a pharmaceutical composition ina therapeutically effective amount. A therapeutically effective amountis an amount that results in a discernible patient benefit, such asincreased healing of a disease or disorder associated with pathogenicMCH receptor, as described herein. A preferred concentration is onesufficient to inhibit the binding of MCH to MCHR1 receptor in vitro.Compositions providing dosage levels ranging from about 0.1 mg to about140 mg per kilogram of body weight per day are preferred (about 0.5 mgto about 7 g per human patient per day). The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. Dosage unit forms will generally contain betweenfrom about 1 mg to about 500 mg of an active ingredient. It will beunderstood, however, that the optimal dose for any particular patientwill depend upon a variety of factors, including the activity of thespecific compound employed; the age, body weight, general health, sexand diet of the patient; the time and route of administration; the rateof excretion; any simultaneous treatment, such as a drug combination;and the type and severity of the particular disease undergoingtreatment. Optimal dosages may be established using routine testing, andprocedures that are well known in the art.

Pharmaceutical compositions may be packaged for treating disordersresponsive to melanin concentrating hormone receptor modulation (e.g.,treatment of metabolic disorders such as diabetes, heart disease,stroke, eating disorders such as obesity or bulimia, or sexual disorderssuch as anorgasmic or psychogenic impotence). Packaged pharmaceuticalcompositions include a container holding a therapeutically effectiveamount of at least one MCH receptor modulator as described herein andinstructions (e.g., labeling) indicating that the contained compositionis to be used for treating a disorder responsive to MCH receptormodulation in the patient.

Methods of Use

Within certain aspects, the present invention provides methods forinhibiting the development of a disease or disorder associated withpathogenic MCH receptor. In other words, therapeutic methods providedherein may be used to treat a disease, or may be used to prevent ordelay the onset of such a disease in a patient who is free of detectabledisease that is associated with pathogenic MCH receptor. As used herein,a disease or disorder is “associated with pathogenic MCH receptor” if itis characterized by inappropriate stimulation of MCH receptor,regardless of the amount of MCH present locally. Such conditionsinclude, for example, metabolic disorders (such as diabetes), heartdisease, stroke, eating disorders (such as obesity and bulimia nervosa),or sexual disorders such as anorgasmic or psychogenic impotence. Theseconditions may be diagnosed and monitored using criteria that have beenestablished in the art. Patients may include humans, domesticatedcompanion animals (pets, such as dogs) and livestock animals, withdosages and treatment regimes as described above.

Frequency of dosage may vary depending on the compound used and theparticular disease to be treated or prevented. In general, for treatmentof most disorders, a dosage regimen of 4 times daily or less ispreferred. For the treatment of eating disorders, including obesity, adosage regimen of 1 or 2 times daily is particularly preferred. For thetreatment of impotence a single dose that rapidly reaches effectiveconcentrations is desirable. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, and rate of excretion, drugcombination and the severity of the particular disease undergoingtherapy. In general, the use of the minimum dosage that is sufficient toprovide effective therapy is preferred. Patients may generally bemonitored for therapeutic effectiveness using assays suitable for thecondition being treated or prevented, which will be familiar to those ofordinary skill in the art.

Within separate aspects, the present invention provides a variety of invitro uses for the compounds provided herein. For example, suchcompounds may be used as probes for the detection and localization ofMCH receptors, in samples such as tissue sections, as positive controlsin assays for receptor activity, as standards and reagents fordetermining the ability of a candidate agent to bind to MCH receptor, oras radiotracers for positron emission tomography (PET) imaging or forsingle photon emission computerized tomography (SPECT). Such assays canbe used to characterize MCH receptors in living subjects. Such compoundsare also useful as standards and reagents in determining the ability ofa potential pharmaceutical to bind to melanin concentrating hormonereceptor.

Within methods for determining the presence or absence of MCH receptorin a sample, a sample may be incubated with a compound as providedherein under conditions that permit binding of the compound to MCHreceptor. The amount of compound bound to MCH receptor in the sample isthen detected. For example, a compound may be labeled using any of avariety of well known techniques (e.g., radiolabeled with a radionuclidesuch as tritium, as described herein), and incubated with the sample(which may be, for example, a preparation of cultured cells, a tissuepreparation or a fraction thereof). A suitable incubation time maygenerally be determined by assaying the level of binding that occursover a period of time. Following incubation, unbound compound isremoved, and bound compound detected using any method for the labelemployed (e.g., autoradiography or scintillation counting forradiolabeled compounds; spectroscopic methods may be used to detectluminescent groups and fluorescent groups). As a control, a matchedsample may be simultaneously contacted with radiolabeled compound and agreater amount of unlabeled compound. Unbound labeled and unlabeledcompound is then removed in the same fashion, and bound label isdetected. A greater amount of detectable label in the test sample thanin the control indicates the presence of capsaicin receptor in thesample. Detection assays, including receptor autoradiography (receptormapping) of MCH receptors in cultured cells or tissue samples may beperformed as described by Kuhar in sections 8.1.1 to 8.1.9 of CurrentProtocols in Pharmacology (1998) John Wiley & Sons, New York.

Modulators provided herein may also be used within a variety of wellknown cell culture and cell separation methods. For example, modulatorsmay be linked to the interior surface of a tissue culture plate or othercell culture support, for use in immobilizing MCH receptor-expressingcells for screens, assays and growth in culture. Such linkage may beperformed by any suitable technique, such as the methods describedabove, as well as other standard techniques. Modulators may also be usedto facilitate cell identification and sorting in vitro, permitting theselection of cells expressing a MCH receptor. Preferably, themodulator(s) for use in such methods are labeled as described herein.Within one preferred embodiment, a modulator linked to a fluorescentmarker, such as fluorescein, is contacted with the cells, which are thenanalyzed by fluorescence activated cell sorting (FACS).

Within other aspects, methods are provided for modulating binding of MCHto an MCH receptor in vitro or in vivo, comprising contacting a MCHreceptor with a sufficient amount of a modulator provided herein, underconditions suitable for binding of MCH to the receptor. Preferably,within such methods, MCH binding to receptor is inhibited by themodulator. The MCH receptor may be present in solution, in a cultured orisolated cell preparation or within a patient. Preferably, the MCHreceptor is a MCHR1 receptor present in the hypothalamus. In general,the amount of compound contacted with the receptor should be sufficientto modulate MCH binding to MCH receptor in vitro within, for example, abinding assay as described in Example 2. MCH receptor preparations usedto determine in vitro binding may be obtained from a variety of sources,such as from HEK 293 cells or Chinese Hamster Ovary (CHO) cellstransfected with a MCH receptor expression vector, as described herein.

Also provided herein are methods for modulating the signal-transducingactivity of cellular MCH receptors, by contacting MCH receptor, eitherin vitro or in vivo, with a sufficient amount of a modulator asdescribed above, under conditions suitable for binding of MCH to thereceptor. Preferably, within such methods, signal-transducing activityis inhibited by the modulator. The MCH receptor may be present insolution, in a cultured or isolated cell preparation or within apatient. In general, the amount of modulator contacted with the receptorshould be sufficient to modulate MCH receptor signal transducingactivity in vitro within, for example, a calcium mobilization assay asdescribed in Example 3. An effect on signal-transducing activity may beassessed as an alteration in the electrophysiology of the cells, usingstandard techniques, such as intracellular patch clamp recording orpatch clamp recording. If the receptor is present in an animal, analteration in the electrophysiology of the cell may be detected as achange in the animal's feeding behavior.

The following Examples are offered by way of illustration and not by wayof limitation. Unless otherwise specified all reagents and solvent areof standard commercial grade and are used without further purification.

EXAMPLES Example 1 Preparation of Representative 1-Benzyl-4-ArylPiperazines

This Example illustrates the synthesis of representative 1-benzyl-4-arylpiperazines. It will be apparent that, through variation of startingcompounds, these methods may be used to prepare a wide variety of suchcompounds. References to schemes within this Example refer to SchemesA-K, discussed above.I. 1-(5-bromo-6-methoxypyridin-2-yl)-4-(3,4-dimethoxybenzyl)piperazinevia Scheme A

A quantity of 0.1 g (0.4 mmole, 1 eq) of1-(5-Bromo-6-methoxy-pyridin-2-yl)-piperazine and 0.061 g (0.4 mmole, 1eq) of 3,4-dimethoxybenzaldehyde is dissolved in 5 mL of anhydroustoluene, and 3 drops of glacial acetic acid is added. An excess ofNaBH(OAc)₃ is added to the solution and stirred at room temperatureunder a nitrogen atmosphere until no starting material is detectable byTLC. At that time the reaction is quenched with saturated aqueous NaHCO₃and extracted with ethyl acetate. The ethyl acetate extracts are driedover anhydrous MgSO₄ and concentrated in vacuo. The residue ischromatographed on SiO₂ with 10% CH₃OH (2M NH₃)/CH₂Cl₂ to afford1-(5-bromo-6-methoxypyridin-2-yl)-4-(3,4-dimethoxybenzyl)piperazine(compound 1). Analysis: ¹H NMR (400 MHz, DMSO): 7.71 (1H, d), 7.36 (1H,s), 7.05 (2H, m), 6.39 (1H, d), 4.38 (4H, m), 3.80 (9H, m), 3.39 (4H,m), 3.02 (2H, m). MS (LC-MS): Calculated for C₁₉H₂₄BrN₃O₃ 422.32, found436.3424.31 (M+2).II.1-(4-Chloro-3-trifluoromethyl-phenyl)-4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazinevia Scheme B

A quantity of 0.17 g (0.6 mmole, 1 eq) of1-(4-chloro-3-trifluoromethyl-phenyl)-piperazine and 0.1 g (0.6 mmole, 1eq) of 3,4-dimethoxyacetophenone and 2 mL of Ti(OiPr)₄ are warmed to 70°C. for 2 hours. The reaction solution is cooled to room temperature and20 mL of anhydrous methanol is added followed by 1.0 g of NaBH₄ and theresulting solution is stirred at room temperature for 2 hours. Thereaction is quenched by the addition of 1 N NaOH and extracted withCH₂Cl₂. The CH₂Cl₂ extracts are dried over anhydrous MgSO₄ andconcentrated in vacuo. The residue is chromatographed on SiO₂ with ethylto afford1-[4-chloro-3-(trifluoromethyl)phenyl]-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine(compound 2). Analysis ¹H NMR (400 MHz, CDCl₃): 7.31 (1H, d), 7.19 (1H,m), 6.90 (4H, m), 3.89 (6H, d), 3.38 (1H, m), 3.20 (4H, m), 2.61 (4H,m). MS (LC-MS): Calculated for C₂₁H₂₄ClF₃N₂O₂ 428.88, found 429.30 (M+).III. 3-{1-[4-(4-Bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethyl}-quinolinevia Scheme C

A solution containing 3-quinolinecarboxaldehyde (25 mg, 0.16 mmol, 1.0equivalents), benzotriazole (19 mg, 0.16 mmol, 1.0 equivalents) and1-(4-bromo-3-methoxy-phenyl)-piperazine (39 mg, 0.17 mmol, 1.1equivalents) in ethanol (1 ml) and toluene (2 ml) was heated 20 minutesat 60° C. Solution was concentrated. Residue was coevaporated withtoluene, then dissolved in THF and treated with 3.0 M solution of methylmagnesium bromide in diethyl ether (0.13 ml, 0.4 mmol, 2.5 equivalents).The reaction was stirred 18 hours at room temperature. The reaction wasdiluted with ethyl acetate and washed twice with 1N NaOH, brine, dried(MgSO4), filtered and concentrated. The residue was purified bypreparative TLC to afford3-{1-[4-(4-Bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethyl}-quinoline(compound 3). Yield: 41 mg, 81%. Analysis H¹ NMR (400 MHz, CDCl₃): 8.96(1H, s), 8.08 (2H, m), 7.82 (1H, d), 7.70 (1H, t), 7.56 (1H, t), 7.34(1H, d), 6.45 (1H, m), 6.36 (1H, dd), 3.85 (3H, s), 3.68 (1H, q), 3.18(4H, m), 2.73 (2H, m), 2.60 (2H, m), 1.54 (3H, d).

MS (LC-MS): Calculated for C22H24BrN3O 426.11, found, 426.14 and 428.14,M+2.IV.(R)-1-(4-Chloro-3-Methoxy-Phenyl)-4-[1-(3,4-Dimethoxy-Phenyl)-Ethyl]-piperazine

A quantity of 40 g (0.22 moles, 1 eq) of1-(3,4-dimethoxy-phenyl)-ethanone, 35 g (0.22 moles, 1.0 eq) ofpiperazine-1 carboxylic acid ethyl ester and 125 mL (0.44 moles, 2.0 eq)of Titanium (IV) isopropoxide were stirred at 70° C. under N₂ overnight.The reaction mixture was cooled to 0° C., 200 mL of MeOH was added, andthen 9.1 g of NaBH₄ was added carefully. Then the reaction mixture wasstirred at room temperature overnight. The reaction was quenched with250 mL of 1N NaOH and extracted with dichloromethane. The extract waswashed with brine, dried over Na₂SO₄ and concentrated to give 70 g ofyellowish oil.

The crude oil was dissolved in 250 mL of ethanol and 125 mL of waterwith 100 g of KOH. The mixture was heated under reflux over night. Thesolvent was removed and the residue was dissolved in 1 N HCl and washedwith ethyl acetate. The aqueous layer was basified with 1 N NaOH andextracted with ethyl acetate. The extract was washed with brine, driedover Na₂SO₄ and concentrated to yield yellowish oil (38 g, 65%).Analysis: MS (LC-MS): Calculated for C₁₄H₂₂N₂O₂ 250.17, found 251.27(M+).

A quantity of 39 g (0.15 mole, 1 eq) of1-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine was dissolved in 150 mL oftert-butyl methyl ether and 150 mL of methanol, and warmed at 45° C. Tothis solution, a solution of 11.7 g (0.076 mole, 0.5 eq) of L-tartaricAcid in 50 mL of tert-Butyl methyl ether and 30 mL of methanol that waswarmed at 40° C. was added slowly. After cooling down slowly andstanding at room temperature overnight, the white precipitate wascollected by filtration, giving 26 g solid product. The solid wasrecrystallized from 300 mL of 90% methanol-water twice to afford 12 g ofwhite solid, which was converted to 7.4 g of free base (38% recovery).Analysis: ¹H NMR (300 MHz, CDCl₃): 6.86 (1H, s), 6.79 (2H, d), 3.85 (6H,d), 3.24 (1H, q), 2.84 (4H, t), 2.35 (4H, m) and 1.32 (3H, d). MS(LC-MS): Calculated for C₁₄H₂₂N₂O₂ 250.17, found 251.27 (M+). The chiralpurity of the product was identified 100% with its Mosher's amidederivative and detected with chiral HPLC.

A quantity of 4.2 g (17 mmoles, 1 eq) of(R)-1-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine and 4.4 g (20 mmoles,1.2 eq) of 5-Bromo-2-chloro-anisole was dissolved in 110 mL of anhydroustoluene, and the solution is purged with N₂ for 20 minutes. To thesolution was added 0.33 g (0.5 mmoles, 0.03 eq) ofrac-2,2′-Bis(diphenyl-phosphino)-1,1′-binapphtyl, 0.031 g (0.34 mmole,0.02eq) of tris(dibenzylideneacetone)-dipalladium(0) and 2.4 g (22mmoles, 1.3 eq) of potassium tert-butoxide in order. The mixture washeated at 80° C. under N₂ overnight. After cooled down, the reaction wasfiltered through Celite. The organic solution is washed with 1N NaOH andbrine, dried over Na₂SO₄ and concentrated. The residue was purified byflash chromatography on silica gel eluted with 1:1 ethyl acetate:hexanesto afford brownish oil. The product (compound 4) was converted to itsHCl salt, giving yellowish solid (4.1 g, 53%). Mp: 172-6° C. Analysis:¹H NMR (300 MHz, DMSO): 11.8 (1H, s), 9.2 (1H, s), 7.48 (1H, s),7.21(1H, d), 7.12 (1H, dd), 6.99 (1H, d), 6.68 (1 h, d), 6.59 (1H, dd),4.42 (1H, t), 3.80 (12H, m), 3.39 (1H, t), 3.19 (1H, t), 2.99 (3H, m),1.73 (3H, d). MS (LC-MS): Calculated for C₂₁H₂₇ClN₂O₃ 390.90, found391.38 (M+).V.(6R,10S)-2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazinevia Scheme E

Solid di-t-butyl dicarbonate (16.68 g, 76.43 mmol, 1.10 equivalents) wasadded in aliquots over 30 minutes to an ice chilled solution ofL-2-amino-pent-4-enoic acid (8.0 g, 69.48 g, 1.0 equivalents) in 1N NaOH(140 ml) and dioxane (140 ml). The ice bath was removed and the reactionwas stirred at room temperature for 4 hours. The reaction solution wasconcentrated. The aqueous residue was chilled on ice, layered with EtOAcand acidified with ice cold 1N HCl to pH 2. The aqueous residue wasextracted with EtOAc twice. The combined EtOAc extracts were washed withbrine, dried with MgSO4, filtered and concentrated to a clear liquid(14.9 g, 100% yield). Analysis H¹ NMR (400 MHz, CDCl₃): 5.72 (1H, m),5.18 (2H, m), 5.06 (1H, broad d), 4.38 (1H, m), 2.54 (2H, m), 1.38 (9H,s).

LC-MS: base peak 116, M+1—CO₂C(CH3)₃.

A solution of L-2-tert-butoxycarbonylamino-pent-4-enoic acid (1.55 g,7.23 mmol., 1.0 equivalents),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.525g, 7.95 mmol, 1.1 equivalents), 4-chloro-3-methoxyaniline (1.135 g, 7.23mmol, 1.0 equivalents) in pyridine (20 ml) was stirred for 18 hours atroom temperature. The reaction was concentrated. The residue was dilutedwith EtOAc and washed with water. The aqueous was extracted with EtOAc.The combined EtOAc extracts were washed with brine, dried with MgSO4,filtered and concentrated. The residue was triturated with diethylether. The beige solid (1.85 g, 5.21 mmol, 72% yield) was collected byfiltration. Analysis H₁NMR (400 MHz, CDCl₃): 8.5 (1H, broad s), 7.49(1H, d), 7.22 (1H, m), 6.79 (1H, dd), 5.83 (1H, m), 5.23 (2H, m), 5.00(1H, broad s), 4.28 (1H, m), 3.89 (3H, s), 2.57 (2H, m), 1.25 (9H, s).

MS (LC-MS): Calculated for C17H23ClN2O4 354.1, found 355.25 (M+).

To ice chilled(S)[1-(4-chloro-3-methoxy-phenylcarbamoyl)-but-3-enyl]-carbamic acidtert-butyl ester (7.75 g, 22.40 mmol, 1.0 equivalents) in toluene (112ml) was added a 0.5M solution of alane-N,N-dimethylethylamine complex intoluene(141 ml, 70.56 mmol, 3.13 mmol). Following addition, the reactionwas stirred at room temperature for 18 hours. 26 The reaction wasquenched at 0° C. by the addition of 1N NaOH. The mixture was filteredthrough Celite and extracted 3 times with EtOAc. The EtOAc extracts werewashed with brine, dried with MgSO4, filtered, concentrated andcoevaporated with toluene. The alane reduction was repeated on theresidue by the same procedure using the crude reaction product, toluene(112 ml) and 0.5M solution of alane-N,N-dimethylethylamine complex intoluene (70 ml, 35.o mmol, 1.56 equivalents). Work-up the same way toobtain product as an oil (7.62 g, 22.35 mmol, 100% yield). AnalysisH₁NMR (400 MHz, CDCl₃): 7.09 (1H, d), 6.21 (1H, broad s), 6.14 (1H, dd),5.78 (1H, m), 5.18 (2H, m), 4.50 (1H, broad s), 4.23 (1H, broad s), 3.88(3H, s), 3.18 (2H, m), 2.32 (2H, m), 1.39 (9H, s). MS (LC-MS):

Calculated for C17H25ClN2O3 340.16, found 341.25 (M+).

To an ice chilled biphasic solution containing(S){1-[(4-chloro-3-methoxy-phenylamino)-methyl]-but-3-enyl}-carbamicacid tert-butyl ester (7.00 g, 20.53 mmol, 1.0 equivalents) in EtOAc (95ml) and saturated sodium bicarbonate (122 ml) was added a solution ofchloroacetylchloride (1.96 ml, 24.64 mmol, 1.2 equivalents). Followingthe addition, the reaction was stirred for 30 minutes at roomtemperature. The layers were separated. The aqueous was extracted withEtOAc. The combined EtOAc extracts were washed with brine, dried withMgSO4, filtered and concentrated to give an oil (7.58 g, 18.22 mmol, 89%yield). Analysis H¹ NMR (400 MHz, CDCl₃): 7.42 (1H, d), 7.02 (1H, broads), 6.82 (1H, m), 5.70 (1H, m), 5.09 (2H, m), 4.80 (1H, d), 4.30 (1H,m), 3.94 (4H, m), 3.80 (2H, s), 3.11 (1H, m), 2.20 (2H, m), 1.42 (9H,s). MS (LC-MS): Calculated for C₁₉H₂₆Cl₂N₂O₄ 416.13, found 417.19 (M+).

To an ice chilled solution containing(S)1-{[(2-chloro-acetyl)-(4-chloro-3-methoxy-phenyl)-amino]-methyl}-but-3-enyl)-carbamicacid tert-butyl ester (7.58 g, 18.22 mmol, 1.0 equivalents) was addedtrifluoroacetic acid dropwise. The reaction was stirred on ice for 30minutes. The reaction was concentrated. The residue was dissolved in DMF(455 ml) and triethylamine (12.75 ml, 90.91 mmol, 5.0 equivalents) andstirred at 50° C. for 5 hours. The reaction was concentrated. Theresidue was subjected to acid base extraction to remove neutralbyproducts. The residue was partitioned between 1N HCl and EtOAc. Theaqueous was extracted with EtOAc. The EtOAc extracts were discarded. Theaqueous was basified and extracted with dichloromethane. Thedichloromethane extracts were dried with MgSO4, filtered andconcentrated to an oil (4.0 g, 14.28 mmol, 78% yield). Analysis H¹ NMR(400 MHz, CDCl₃): 7.36 (1H, d), 6.85 (1H, m), 6.77 (1H, dd), 5.78 (1H,m), 5.19 (2H, m), 3.90 (3H, s), 3.73 (2H, dd), 3.50 (2H, m), 3.22 (1H,m), 2.29 (2H, m). MS (LC-MS): Calculated for C14H17ClN2O2 280.10, found281.15 (M+).

To an ice chilled solution containing(S)5-allyl-1-(4-chloro-3-methoxy-phenyl)-piperazin-2-one (4.00 g, 14.28mmol, 1.0 equivalents) in toluene (50 ml) was added dropwise a 0.5Msolution of alane-N,N-dimethylethylamine complex in toluene (86 ml,42.86 mmol, 3.0 equivalents). Following addition, the reaction wasstirred at room temperature over night for 18 hours. The reaction wasquenched at 0° C. with 1N NaOH, extracted with EtOAc twice anddichloromethane twice. Organic extracts were dried with MgSO4, filteredand concentrated to an oil (3.80 g, 14.28 mmol, 100% yield). Analysis H¹NMR (400 MHz, CDCl₃): 7.20 (1H, d), 6.48 (1H, m), 6.43 (1H, dd), 5.82(1H, m), 5.14 (2H, m), 3.88 (3H, s), 3.47 (2H, d), 3.12 (1H, m), 2.96(1H, dt), 2.90 (1H, m), 2.89 (1H, dt), 2.45 (1H, t), 2.26 (1H, m), 2.22(11H, m). MS (LC-MS): Calculated for C14H19ClN2O266.12, found 267.19(M+).

A solution containing(S)3-allyl-1-(4-chloro-3-methoxy-phenyl)-piperazine (3.81 g, 14.28 mmol,1.0 equivalents) and di-t-butyldicarbonate (3.428 g, 15.71 mmol, 1.1equivalents) in THF (71 ml) was stirred at room temperature for 18hours. The solution was concentrated to an oil (5.23 g, 14.28 mmol, 100%yield.) Analysis H¹ NMR (400 MHz, CDCl₃): 7.19 (1H, d), 6.45 (1H, m),6.38 (1H, dd), 5.82 (1H, m), 5.11 (2H, m), 4.23 (1H, broad s), 4.00 (1H,m), 3.87 (3H, s), 3.42 (2H, m), 3.19 (1H, m), 2.84 (1H, dd), 2.74 (1H,dt), 2.50 (2H, m), 1.48 (9H, s). MS (LC-MS): Calculated for C₁₉H₂₇ClN₂O₃366.17, found 367.18 (M+).

To a solution of(S)2-allyl-4-(4-chloro-3-methoxy-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (5.23 g, 14.28 mmol, 1.0 equivalents) in DMF (39 ml)and water (5.5 ml) were added palladium (II) chloride (2.616 g, 14.75mmol, 1.03 equivalents), copper (I) chloride (1.460 g, 14.75 mmol, 1.03equivalents). Oxygen gas was bubbled into the solution. The reaction wasstirred under oxygen balloon for 18 hours at room temperature. Themixture was filtered through Celite. The filtrated was partitionedbetween EtOAc and water. The aqueous was extracted with EtOAc. Thecombined EtOAc extracts were washed with brine, dried with MgSO4,filtered and concentrated. The residue was purified by flashchromatography on silica gel eluted with 50% EtOAc: Hexanes. The productwas a yellow oil (3.45 g, 9.07 mmol, 63% yield). Analysis H¹ NMR (400MHz, CDCl₃): 7.19 (1H, d), 6.44 (1H, m), 6.36 (1H, dd), 4.61 (1H, broads), 3.99 (1H, m), 3.87 (3H, s), 3.48 (2H, m), 3.16 (2H, m), 2.93 (1H,dd), 2.88 (1H, dt), 2.68 (1H, m), 2.19 (3H, s), 1.60 (9H, s). MS(LC-MS): Calculated for C19H27ClN2O4 382.17, found 383.17 (M+). Thechiral purity was assessed by chiral HPLC. A racemic standard showed a1:1 mixture of 2 peaks with retention times 10.64 and 12.13 minutes.Analysis of the ketone synthesized from L-allylglycine showed only 1peak at 10.64 minutes and none of the enantiomer.

To an ice chilled solution of(S)4-(4-chloro-3-methoxy-phenyl)-2-(2-oxo-propyl)-piperazine-1-carboxylicacid tert-butyl ester (363 mg g, 0.955 mmol, 1.0 equivalents) indichloromethane (4 ml) was added trifluoroacetic acid (4 ml). Thereaction was stirred on ice for 30 minutes and then concentrated. Theresidue was dissolved in methanol (8 ml) and chilled on ice. To thissolution was added 3,4-dimethoxybenzaldehyde (206 mg, 1.24 mmol, 1.3equivalents) and 6N NaOH (0.96 ml, 5.73 mmol, 6.0 equivalents). Thereaction was stirred at 55° C. over night. The reaction wasconcentrated. The residue was partitioned between 1N NaOH anddichloromethane. The aqueous was extracted with dichloromethane. Theorganic extracts were dried with MgSO4, filtered and concentrated. Theresidue was purified by flash chromatography on silica gel eluted with2.5% methanol/dichloromethane. The product was obtained as a white foam(115 mg, 0.27 mmol, 29% yield). Analysis H¹ NMR (400 MHz, CDCl₃): 7.19(1H, d), 6.86 (3H, m), 6.46 (1H, m), 6.41 (1H, dd), 3.91 (3H, s), 3.89(3H, s), 3.87 (3H, s), 3.44 (2H, m), 3.30 (2H, dd), 2.78 (4H, m), 2.50(3H, m), 2.08 (1H, td). MS (LC-MS): Calculated for C23H27ClN2O4 430.17,found 431.15, (M+). Additional fragmentation products resulting fromdecomposition in mobile phase were observed.

To a solution of (6R,10S)₂-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one(38 mg, 0.09 mmol, 1.0 equivalents) was added p-toluenesulfonylhydrazide (21 mg, 1.3 equivalents). The reaction was stirred atroom temperature for 18 hours. Sodium borohydride (34 mg, 0.89 mmol,10.0 equivalents) was added. The reaction was stirred under reflux at65° C. for 4 hours. The reaction was quenched with 10% ammonium chlorideand partitioned between 1N NaOH and dichloromethane. The organic extractwas washed with brine, dried with MgSO4, filtered and concentrated. Theresidue was purified on a 500 micron preparative TLC plate eluted with1:1 ethyl acetate:hexane. (6R,10S)2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine(compound 5) was obtained as an oil (25 mg, 0.06 mmol, 67% yield).Analysis H¹ NMR (400 MHz, CDCl₃): 7.19 (1H, d), 6.90 (2H, m), 6.45 (1H,m), 6.41 (1Hm dd), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.41 (2H,m), 2.97 (1H, dd), 2.75 (1H, m), 2.62 (1H, m), 2.37 (1H, m), 2.03 (1H,dt), 1.42-1.80 (6H, m). MS (LC-MS): Calculated for C23H29ClN2O₃ 416.19,417.19 (M+).VI. (6R,10S)[6-(3,4-Dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-(4-trifluoromethyl-phenyl)-methanone(via Scheme F)

(S)2-(4-Benzyl-piperazin-2-yl)-ethanol (2.2 g, 10 mmol) was dissolved inanhydrous dichloromethane (100 mL) at room temperature. Di-tert-butyldicarbonate (BOC anhydride) was added (2.20 g, 11 mmol) and theresulting solution was stirred at room temperature overnight. Thereaction was quenched by diluting with brine. The organic phase wasseparated and the aqueous phase was washed with dichloromethane. Theorganic phases were combined and washed with brine (2×50 mL), dried(MgSO₄), and filtered. Solvent removal under reduced pressure afforded4-benzyl-2-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butylester as a clear oil (3.13 g, 98% yield). MS: 320 (M+). H-1 NMR (400MHz, CDCl₃): 7.3 (5H, br), 4.28 (1H, br), 4.0 (1H, br), 3.8 (1H, br),3.6 (1H, br), 3.5 (2H, br), 3.4 (1H, m), 3.0 (1H, t), 2.6-2.8 (2H, br),2.22 (1H, dd, J=4; 11.4 Hz) 2.02 (1H, dt, J=3.5; 11.7 Hz), 1.46 (s, 9H).

Under nitrogen atmosphere (balloon),(S)4-benzyl-2-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butylester (3.1 g, 97 mmol) was dissolved in anhydrous dichloromethane (100mL) containing previously activated 4 Å molecular sieves (1.0 g) and4-methylmorpholine N-oxide (13 mmol, 1.5 g). The reaction started byaddition of tetrapropylammonium perruthenate (150 mg, 0.15 mmol). After1 hour, LC/MS analysis showed no remaining starting material. The blacksuspension was filtered through a silicagel plug and the desired productwas eluted with 5% methanol in chloroform. Solvent evaporation underreduced pressure provided4-benzyl-2-(2-oxo-ethyl)-piperazine-1-carboxylic acid tert-butyl esteras a clear oil (2.9 g, 94% yield). MS: 318 (M+). H-1 NMR significantsignals (400 MHz, CDCl₃): 9.78 (1H, t, J=2.4 Hz), 7.25 (5H, s), 3.68(2H, t, 3 Hz), 3.48 (1H, d, J=13.2), 3.36 (1H, d, J=13.2 Hz), 2.2 (1H,dd, J=4; 11 Hz), 2.08 (1H, dt, J=3.5, 11.7 Hz), 1.44 (9H, s).

(S)4-benzyl-2-(2-oxo-ethyl)-piperazine-1-carboxylic acid tert-butylester (2.9 g, 9.1 mmol) was dissolved in anhydrous tetrahydrofuran (100mL) at 0° C. under an atmosphere of nitrogen (balloon). Methyl magnesiumbromide (12 mmol, 3.0 M solution in THF, 4.0 mL) was added dropwise andthe reaction was taken to room temperature. After 3 hours, the reactionwas taken to 0° C. and quenched by dropwise addition of saturatedaqueous ammonium chloride solution. The phases were separated, and theorganic layer was washed with brine (2×100 mL), dried (MgSO₄) andfiltered. Solvent evaporation under reduced pressure produced the crude4-benzyl-2-(2-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butylester as a mixture of diastereoisomers (2.8 g, 85% yield). MS: 334 (M).H-1 NMR significant signals (400 MHz, CDCl₃): 7.27 (5H, s), 1.44 (9H,s), 1.17 and 1.18 (d, 3H combined).

Under nitrogen atmosphere (balloon),(S)4-benzyl-2-(2-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butylester (2.8 g, 97 mmol) was dissolved in anhydrous dichloromethane (90mL) containing previously activated 4 Å molecular sieves (1.0 g) and4-methylmorpholine N-oxide (13 mmol, 1.5 g). The reaction started byaddition of tetrapropylammonium perruthenate (200 mg, 0.2 mmol). After 1hour LC/MS analysis showed no remaining starting material. The blacksuspension was filtered through a silicagel plug. Solvent evaporationunder reduced pressure provided the crude product as a brown oil (2.7g). Purification was carried out by flash chromatography, which yielded1.4 g (43% yield) of 4-benzyl-2-(2-oxo-propyl)-piperazine-1-carboxylicacid tert-butyl ester as an oil. MS: 318 (M+). H-1 NMR significantsignals (400 MHz, CDCl₃): 7.25 (5H, s), 3.38 (1H, d, J=13.2), 3.36 (1H,d, J=13.2 Hz), 2.1 (3H, s), 1.42 (9H, s). C-13 NMR significant signals(100 MHz, CDCl₃): 206.8 ppm.

To an ice chilled solution containing(S)4-benzyl-2-(2-oxo-propyl)-piperazine-1-carboxylic acid tert-butylester (199 mg, 0.60 mmol, 1.0 equivalents) in dichloromethane (4 ml) wasadded trifluoroacetic acid (4 ml). The reaction was stirred at 0° C. for30 minutes, concentrated and coevaporated with toluene. The residue wasdissolved in methanol (5 ml). To this solution at room temperature wasadded 3,4-dimethoxybenzaldehyde (130 mg, 0.78 mmol, 1.3 equivalents) and6N NaOH (0.6 ml, 3.6 mmol, 6.0 equivalents). The reaction was heated at55° C. for 15 hours. The reaction partitioned between dichloromethaneand 1N NaOH. The aqueous phase was extracted with dichloromethane. Thedichloromethane extracts were washed with brine, dried with MgSO₄,filtered and concentrated. The residue was purified on two 1000 micronpreparative TLC plates eluted with 4% MeOH/dichloromethane. Obtained 44mg of the cis stereoisomer (0.12 mmol, 19% yield) and 16 mg of the transstereoisomer (0.04 mmol, 7% yield.) Analysis H¹ NMR (400 MHz, CDCl₃) ofcis product: 7.29 (5H, m), 6.86 (3H, m), 3.89 (3H, s), 3.87 (3H, 3H),3.50 (2H, m), 3.25 (1H, dd), 2.67 (4H, m), 2.44 (2H, m), 2.28 (m, 1H),2.08 (3H, m). MS (LC-MS): Calculated for C23H28N2O3 380.21, found 381.20(M+).

A solution of2-benzyl-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one(43 mg, 0.11 mmol, 1.0 equivalents) and p-toluenesulfonylhydrazide (27mg, 0.15 mmol, 1.3 equivalents) in methanol (1.0 ml) was stirred at roomtemperature for 15 hours. Sodium borohydride (43 mg, 1.1 mmol, 10.0equivalents) was heated under reflux at 65° C. Since TLC indicatedreaction was not complete after 5 hours, additional sodium borohydride(52 mg, 1.37 mmol, 12 equivalents) was added and the reaction wasstirred at 65° C. for 18 hours. The reaction was partitioned between 1NNaOH and dichloromethane. The aqueous was extracted withdichloromethane. The dichloromethane was washed with brine, dried withMgSO4, filtered and concentrated. The residue was purified on a 500micron preparative TLC eluted with (4% MeOH/dichloromethane), and 14 mg(6R,10S)2-benzyl-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazinewas obtained (0.04 mmol, 38% yield). Analysis H¹ NMR (400 MHz, CDCl₃):7.29 (5H, m), 6.80 (3H, m), 3.88 (3H, s), 3.86 (3H, s), 3.48 (2H, m),2.89 (1H, broad d), 2.65 (2H, m), 2.54 (1H, broad d), 2.22 (1H, m), 2.05(1H, m), 1.96 (2H, m), 1.54 (6H, m). MS (LC-MS): Calculated forC23H30N2O2 366.23, found 367.26 (M+).

A solution of(6R,10S)₂-benzyl-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine(14 mg, 0.04 mmol), 10% Pd/C (3 mg), and ammonium formate (12 mg, 0.19mmol) was heated under reflux for 6 hours. Additional ammonium formate(11 mg, 0.17 mmol) and the reaction was stirred under reflux for 15hours. The reaction was filtered through Celite. The filtrate wasconcentrated. The residue was dissolved in dichloromethane (0.5 ml) andtreated with triethylamine (42 microliters, 0.19 mmol, 5.0 equivalents)and trifluoromethylbenzoylchloride (4 microliters, 0.03 mmol, 1.5equivalents). The reaction was stirred for 1 hour at room temperature.The reaction was transferred to a vial and shaken with ethyl acetate and1N NaOH. The aqueous was extracted again with ethyl acetate. The ethylacetate extracts were concentrated. The residue was purified 250 micronanalytical TLC, yielding 3 mg of(6R,10S)[6-(3,4-Dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-(4-trifluoro-methyl-phenyl)-methanone(compound 6; 0.007 mmol, 18% yield). MS (LC-MS): Calculated forC₂₄H₂₇F₃N₂O₃ 448.20, found 449.15 (M+). Chiral HPLC showed product was97% one enantiomer, 3% opposite enantiomer.VII.(6R,10S)2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-ol

(6R,10S)2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one(20 mg, 0.05 mmol, 1.0 equivalents) and sodium borohydride (9 mg, 0.24mmol, 5.1 equivalents) in methanol (2 ml) were stirred at roomtemperature for 90 minutes. Reaction was quenched with 1N NaOH andextracted with dichloromethane twice. The dichloromethane extracts werewashed with brine, dried (MgSO₄), filtered and concentrated to 15 mgfilm. Yield of2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-ol(compound 7): 75%. Analysis H¹ NMR (400 MHz, CDCl₃): 7.19 (1H, d), 6.87(3H, m), 6.44 (2H, m), 3.89 (3H, s), 3.85 (s, 3H), 3.81 (3H, s), 3.35(2H, m), 2.90 (1H, dd), 2.71 (3H, m), 2.38 (1H, t), 2.04 (3H, m), 1.58(m, 3H). MS (LC-MS): Calculated for C23H29ClN2O4 433.18, 433.4.VIII.8-(4-Chloro-3-methoxy-phenyl)-4-(3,4-dimethoxy-phenyl)-octahydro-pyrazino[2,1-c][1,4]thiazinevia Scheme G

To an ice chilled solution of potassium hydroxide (655 mg, 11.68 mmol,1.0 equivalents) in methanol (32 ml) was addedL-2-tert-butoxycarbonylamino-3-mercapto-propionic acid methyl ester(2.64 ml, 12.85 mmol, 1.1 equivalents). The reaction was stirred on icefor 10 minutes. To the reaction solution was added a solution of2-chloro-1-(3,4-dimethoxy-phenyl)-ethanone (2500 mg, 11.68 mmol, 1.0equivalents) followed by additional THF (7 ml). The reaction was stirredon ice for 4 hours. Solution was concentrated. The residue was extractedwith dichloromethane. The dichloromethane extracts were dried withMgSO₄, filtered and concentrated. The residue was purified by flashchromatography on silica gel eluted with 25% ethyl acetate:hexane.2-tert-Butoxycarbonylamino-3-[2-(3,4-dimethoxy-phenyl)-2-oxo-ethylsulfanyl]-propionicacid methyl ester was obtained as an oil (4.72 g, 98% yield). AnalysisH₁NMR (400 MHz, CDCl₃): 7.55 (2H, m), 6.88 (1H, d), 5.43 (1H, broad d),4.57 (1H, m), 3.95 (3H, s), 3.93 (3H, s), 3.85 (2H, s), 3.73 (3H, s),3.00 (2H, dq), 1.41 (9H, s). MS (LC-MS): Calculated for C19H27NO7S414.15, found 414.21.

To an ice chilled solution of2-tert-butoxycarbonylamino-3-[2-(3,4-dimethoxy-phenyl)-2-oxo-ethylsulfanyl]-propionicacid methyl ester (2.00 g, 9.34 mmol, 1.0 equivalents) indichloromethane (9 ml) was added trifluoroacetic acid (9 ml). Thereaction solution was stirred on ice for 4 hours. The solution wasconcentrated, coevaporated with toluene. The residue was dissolved indichloromethane (30 ml) and chilled on ice. To this was added sodiumtriacetoxyborohydride (2.97 g, 14.02 mmol, 1.5 equivalents) followed bydichloromethane (7 ml). The reaction was stirred 18 hours at roomtemperature. Saturated sodium bicarbonate was added, and the reactionmixture was extracted with dichloromethane. The dichloromethane extractswere dried with MgSO₄, filtered and concentrated.5-(3,4-Dimethoxy-phenyl)-thiomorpholine-3-carboxylic acid methyl esterwas obtained as an oil (1.63 g, 59% yield). Analysis H¹ NMR (400 MHz,CDCl₃): 6.92 (2H, m), 6.83 (1H, d), 3.95 (3H, s), 3.93 (3H, s), 3.87(2H, m), 3.85 (3H, s), 2.77 (3H, m), 2.42 (1H, m). MS (LC-MS):Calculated for C14H19NO4S 297.10, found 298.17.

A 2.0M solution of trimethylaluminum (0.39 ml, 0.78 mmol, 3.5equivalents) was added to a solution of5-(3,4-dimethoxy-phenyl)-thiomorpholine-3-carboxylic acid methyl ester(67 mg, 0.22 mmol, 1.0 equivalents) and 4-chloro-3-methoxyaniline (106mg, 0.68 mmol, 3.0 equivalents). The solution was stirred at 50° C. for18 hours. The reaction was quenched with 1N NaOH and extracted withdichloromethane. The dichloromethane extracts were dried with MgSO₄,filtered and concentrated. The residue was purified on a 1000 micronpreparative TLC. 5-(3,4-Dimethoxy-phenyl)-thiomorpholine-3-carboxylicacid (4-chloro-3-methoxy-phenyl)-amide was obtained as a peach solid (71mg, 76% yield). Analysis H¹ NMR (400 MHz, CDCl₃): 8.61 (1H, s), 7.58(1H, m), 7.26 (1H, m), 6.90 (2H, m), 6.78 (1H, d), 4.04 (1H, m), 3.91(10H, m), 2.98 (1H, m), 2.78 (2H, m), 2.59 (1H, m). MS (LC-MS):Calculated for C20H23ClN2O4S 423.11, found 423.22.

To an ice chilled suspension containing5-(3,4-dimethoxy-phenyl)-thiomorpholine-3-carboxylic acid(4-chloro-3-methoxy-phenyl)-amide n(71 mg, 0.17 mmol, 1.0 equivalents)in toluene (1.5 ml) was added a 0.5M solution of alane (1.6 ml, 0.8mmol, 4.8 equivalents). The reaction was stirred at room temperature for2 hours. The reaction was quenched with 1N NaOH and extracted 3 timeswith dichloromethane. The dichloromethane extracts were dried withMgSO4, filtered and concentrated to yield(4-chloro-3-methoxy-phenyl)-[5-(3,4-dimethoxy-phenyl)-thiomorpholin-3-ylmethyl]-amineas an oil (65 mg, 95% yield). H¹ NMR (400 MHz, CDCl₃): 7.11 (1H, d),6.93 (2H, m), 6.80 (1H, m), 6.19 (m, 2H), 3.86 (10H, m), 3.19 (3H, m),2.80 (2H, m), 2.50 (2H, m). (LC-MS): Calculated for C20H25ClN2O3S409.13, found 409.23.

A solution of(4-chloro-3-methoxy-phenyl)-[5-(3,4-dimethoxy-phenyl)-thiomorpholin-3-ylmethyl]-amine(100 mg, 0.245 mmol, 1.0 equivalents), dibromoethane (0.31 ml, 3.55mmol, 14.5 equivalents) and triethylamine (0.15 ml, 1.09 mmol, 4.5equivalents) in dimethylacetamide (2 ml) was heated at 90° C. for 4hours. Additional dibromoethane (0.16 ml, 1.84 mmol, 7.5 equivalents)and triethylamine (0.25 ml, 1.76 mmol, 7.2 equivalents) was added andreaction was stirred for 4 hours at 90° C. Additional dibromoethane(0.14 ml, 1.62 mmol, 6.6 equivalents) and triethylamine (0.10 ml, 0.71mmol, 2.9 equivalents) were added and reaction was stirred 18 hours at90° C. Reaction was cooled and filtered to remove triethylammoniumhydrobromide. Filtrate was concentrated. Residue was purified on a 1000micron preparative TLC. 34 mg of8-(4-chloro-3-methoxy-phenyl)-4-(3,4-dimethoxy-phenyl)-octahydro-pyrazino[2,1-c][1,4]thiazine(Compound 8) was obtained, along with 36 mg recovered starting material.Yield of product: 32%. H¹ NMR (400 MHz, CDCl₃): 7.19 (1H, d), 6.86 (3H,m), 6.42 (2H, m), 3.89 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.50 (1H,m), 3.19 (2H, dd), 2.92 (1H, m), 2.75 (5H, m), 2.48 (2H, t), 2.15 (1H,dt). MS (LC-MS): Calculated for C22H27ClN2O3S 435.14, 435.24.IX.2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazineVia Scheme H

To a suspension of 2.2 g (0.011 moles, 1 eq) of 5-bromo-piconilic acidin 5 mL of DCM, is added 4.0 mL of thionyl chloride. The mixture isrefluxed for 2.5 hours, and then is concentrated and furtherco-evaporated with toluene. The residue is dissolved in 10 mL of DCM.

A quantity of 2.8 g (0.022 moles, 2.0 eq) of K₂CO₃ and 1 mL (0.01 moles,1.5 eq) of hydroxylethylamine are dissolved in 23 mL of water and cooledin ice bath. The DCM solution prepared above is added slowly, and thereaction is warmed to room temperature and stirred for 2 hours. Thereaction is diluted with DCM and separated. The organic layer is washedwith brine, dried over Na₂SO₄ and concentrated to give6-bromo-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide as a yellowoil (2.3 g, 86%). Analysis: MS (LC-MS): Calculated for C₈H₉BrN₂O₂245.07, found 245.20 (M+) & 247.20 (m+2).

A quantity of 0.25 g (1.0 mmoles, 1 eq) of 6-bromo-pyridine-2-carboxylicacid (2-hydroxy-ethyl)-amide and 0.28 g (1.5 mmoles, 1.5 eq) of3,4-dimethoxyphenyl boronic acid are added in 20 mL of ethylene glycoldimethyl ether with 2 ml of ethanol and 2 ml of 2 M Na₂CO₃. The mixtureis purged with N₂ for 20 minutes, and then 57 mg (0.05 mmoles, 0.05 eq)of Tris (dibenzylideneacetone)-dipalladium (0) is added. The reaction isheated at 80° C. for 6 hours. At that time there is no starting materialshown on TLC. The reaction is filtered through Celite and the solvent isremoved. The residue is taken in ethyl acetate, washed with brine, driedover Na₂SO₄ and concentrated to afford6-(3,4-dimethoxy-phenyl)-pyridine-2-carboxylic acid(2-hydroxy-ethyl)-amide as a yellowish oil (0.21 g, 69%), which is usedin the next step without purification. Analysis: MS (LC-MS): Calculatedfor C₁₆H₁₈N₂O₄302.33, found 303.39 (M+1).

A quantity of 3.0 g (10 mmoles, 1 eq) of6-(3,4-dimethoxy-phenyl)-pyridine-2-carboxylic acid(2-hydroxy-ethyl)-amide and 0.23 g (1.0 mmoles, 0.1 eq) of platinumdioxide are added into 35 mL of ethanol and 2.0 ml concentrated HCl. Thesuspension is hydrogenated under 50 psi of H₂ at room temperatureovernight. After TLC shows no starting material existing, the reactionis filtered through Celite and solvent is removed. The residue is takenin ethyl acetate, washed with saturated Na₂CO₃ and brine, dried overNa₂SO₄ and concentrated to give6-(3,4-dimethoxy-phenyl)-piperidine-2-carboxylic acid(2-hydroxy-ethyl)-amide as a yellowish oil. The oil is triturated withethyl acetate and hexanes to afford a white solid (1.6 g, 52%).Analysis: NMR (300 MHz, CDCl₃): 7.18 (1H, t), 6.90 (2H, m), 6.82 (1H,m), 3.87 (6H, d), 3.66 (3H, m), 3.39 (3H, m), 2.00 (2H, m), 1.80 (1H, m)and 1.22 (2H, m). MS (LC-MS): Calculated for C₁₆H₂₄N₂O₄ 308.37, found309.34 (M+1).

A solution of 1.5 g (5.0 mmoles, 1 eq) of6-(3,4-Dimethoxy-phenyl)-piperidine-2-carboxylic acid(2-hydroxy-ethyl)-amide in 18 mL of THF is added slowly into 15 mL of 1M LiAlH₄ solution in THF. The reaction is heated at 60° C. under N₂ for6 hours. At that time there is no starting material shown on TLC. Cooledin ice bath, to the reaction are added 0.5 ml water, 0.5 mL 15% NaOH and1.5 mL water slowly in order. Finally, some anhydrous MgSO₄ is added,and the reaction mixture is filtered through Celite. Upon the removal ofthe solvent, the residue is taken in ethyl acetate, washed with brine,dried over Na₂SO₄ and concentrated to afford2-{[6-(3,4-dimethoxy-phenyl)-piperidin-2-ylmethyl]-amino}-ethanol as anoil (1.5 g, 68%), which is used in the next step without purification.Analysis: MS (LC-MS): Calculated for C₁₆H₂₆N₂O₃ 294.39, found 295.37(M+1).

To the solution of 3.4 g (11.6 mmoles, 1 eq) of2-{[6-(3,4-dimethoxy-phenyl)-piperidin-2-ylmethyl]-amino}-ethanol and0.20 g (17.5 mmoles, 1.5 eq) of triphenyl phosphine in 120 mL of THF, isadded 1.9 mL (12.7 mmoles, 1.1 eq) of diethyl azodicarboxylate, and thereaction is stirred at room temperature overnight. At that time there isno starting material shown on TLC. After removal of the solvent, theresidue is taken in ethyl acetate and extracted with 1 N HCl solution.The acidic aqueous is basified with 1N NaOH to pH 10, and extracted withdichloromethane 3 times. The organic extracts are washed with brine,dried over Na₂SO₄ and concentrated to give oil product, which ispurified by flash chromatography on silica gel eluted with 50:10:1 DCM:MeOH: NH₄OH, to afford6-(3,4-dimethoxy-phenyl)-octahydropyrido[1,2-a]pyrazine as a brownishstick solid (0.85 g, 27%). Analysis: ¹H NMR (300 MHz, CDCl₃): 6.80 (3H,m), 3.87 (3H, s), 3.84 (3H, s), 3.29 (1H, s), 2.92-2.68 (4H, m), 2.60(2H, m), 2.13 (1H, m), 1.82-1.05 (8H, m). MS (LC-MS): Calculated forC₁₆H₁₈N₂O₄ 302.33, found 303.39 (M+1).

A quantity of 0.85 g (3.0 mmoles, 1 eq) of6-(3,4-dimethoxy-phenyl)-octahydropyrido[1,2-a]pyrazine and 0.76 g (3.4mmoles, 1.1 eq) of 5-bromo-2-chloro-anisole is dissolved in 25 mL ofanhydrous toluene, and the solution is purged with N₂ for 20 min. To thesolution is added 0.18 g (0.30 mmoles, 0.10 eq) ofrac-2,2′-Bis(diphenyl-phosphino)-1,1′-binapphtyl, 0.14 g (0.15 mmole,0.05 eq) of Tris(dibenzylideneacetone)-dipalladium(0) and 0.52 g (4.6mmoles, 1.5 eq) of Potassium tert-butoxide in order. The mixture isheated at 80° C. under N₂ overnight. After it is cooled down, thereaction is filtered through Celite. The organic solution is washed with1N NaOH and brine, dried over Na₂SO₄ and concentrated. The residue ispurified by flash chromatography on silica gel eluted with 50:1dichloromethane: methanol to afford2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine(compound 5) as a brownish stick solid (0.85 g, 68%). Analysis: ¹H NMR(300 MHz, CDCl₃): 7.16 (1H, d), 6.80 (3H, m), 6.40 (2H, m), 3.88 (3H,s), 3.86 (3H, s), 3.85 (3H, s), 3.40 (2H, m), 2.95 (1H, m), 2.70 (3H,m), 2.30 (1H, m), 2.00 (1H, m), 1.82-1.40 (6H, m). MS (LC-MS):Calculated for C₂₃H₂₉ClN₂O₃ 416.94, found 417.23 (M+1).X. (6R,9S)2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrrolo[1,2-a]pyrazinevia Scheme J

A suspension containing (2S)5-oxo-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (10.00 g, 0.044 mol, 1.0 equivalent), benzyl bromide(7.88 g, 0.046 mol, 1.05 equivalents), and potassium carbonate (15.20 g,0.11 mol, 2.5 equivalents) in DMF (200 ml) was allowed to stir at 65° C.overnight. The reaction was allowed to cool to room temperature and themixture was filtered through Celite. The solid was rinsed with ethylacetate (100 ml) and the resulting filtrate was partitioned betweenethyl acetate and saturated brine solution. The organic layer was washedwith saturated brine (3×100 ml), dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The crude, colorless oil was chromatographed onsilica to afford 5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester1-tert-butyl ester as a colorless oil (8.20 g, 0.026 mol, 59% yield).Analysis H¹ NMR (400 MHz, CDCl₃): 7.36 (5H, broad s), 5.20 (2H, d), 4.64(1H, dd), 2.44-1.96 (4H, m), 1.41 (9H, s). MS (LC-MS): Calculated forC17H21NO5 319.14, found 320.19 (M+H)⁺.

A solution of (2S)5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester1-tert-butyl ester (8.20 g, 0.026 mol, 1.0 equivalent) in anhydrous THFwas cooled to 0° C. in an ice bath under N₂. A chilled 0.5M solution of3,4-dimethoxyphenylmagnesium bromide in THF (52.1 mL, 0.026 mol, 1.0equivalent) was slowly added. The reaction mixture was allowed to stirfor two hours. The reaction was quenched upon addition of saturatedNH₄Cl solution (10 ml). The mixture was partitioned between ethylacetate and brine. The organic extract was washed with brine (3×100 ml).The ethyl acetate layer was dried over anhydrous Na₂SO₄ and concentratedin vacuo. The resulting crude blue oil was filtered through a layer ofsilica. The filtrate was concentrated in vacuo to afford2-tert-butoxycarbonylamino-5-(3,4-dimethoxy-phenyl)-5-oxo-pentanoic acidbenzyl ester (10.46 g, 0.023 mol, 88% yield). Analysis H¹ NMR (400 MHz,CDCl₃): 7.5-7.3 (6H, m), 7.0-6.7 (2H, m), 5.2 (2H, m), 4.0-3.8 (6H, m),3.0 (1H, m), 2.6-1.9 (4H, m), 1.4 (9H, s). MS (LC-MS): Calculated forC25H31NO7 457.21, found 458.19 (M+H)⁺.

A solution of(2S)2-tert-butoxycarbonylamino-5-(3,4-dimethoxy-phenyl)-5-oxo-pentanoicacid benzyl ester (10.46 g, 0.023 mol) in dichloromethane (150 ml) wascooled to 0° C. in an ice bath. TFA (40 ml) was slowly added to thestirring mixture and the reaction was allowed to warm to roomtemperature over two hours. The reaction mixture was concentrated invacuo. The resulting residue was dissolved in ethyl acetate and the pHwas adjusted to 7 with 1N NaOH. The organic extract was washed withbrine (100 ml). The ethyl acetate extract was dried over anhydrousNa₂SO₄ and concentrated in vacuo to afford(2S)5-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylic acidbenzyl ester TFA salt (7.24 g, 0.021 mol, 91% yield). MS (LC-MS):Calculated for C20H21NO4 339.15, found 340.16 (M+H)⁺.

(2S)5-(3,4-Dimethoxy-phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylic acidbenzyl ester (7.24 g, 0.021 mol) was dissolved in methanol (100 ml) andadded to a hydrogenation bottle containing Pd/C catalyst (75 mg). Thereaction was hydrogenated at room temperature at 50 psi overnight. Thereaction mixture was filtered through Celite and rinsed withmethanol/ethyl acetate (1:1, 100 ml). The filtrate was concentrated invacuo. The resulting crude residue was triturated with ether and ethylacetate, filtered and dried to afford(2S,5R)5-(3,4-dimethoxy-phenyl)-pyrrolidine-2-carboxylic acid TFA saltas a white solid (3.00 g, 0.012 mol, 57% yield). Analysis H¹ NMR (400MHz, DMSO): 7.18 (1H, s), 6.98 (2H, s), 4.42 (1H, d), 4.64 (1H, dd),3.76 (7H, broad s), 2.24-2.10 (3H, m), 1.74 (1H, m). MS (LC-MS):Calculated for C13H17NO4 251.12, found 252.08 (M+H)⁺.

The (2S,5R)5-(3,4-dimethoxy-phenyl)-pyrrolidine-2-carboxylic acid (3.00g, 0.012 mol, 1.0 equivalent) was suspended in dichloromethane (50 ml)and DIEA (2.50 ml, 0.014 mol, 1.2 equivalents) and cooled to 0° C. in anice bath. A 1.0M solution of Boc anhydride in THF (12.0 ml, 0.012 mol,1.0 equivalent) was added and the reaction was allowed to stir and warmto room temperature overnight. The reaction mixture was washed withbrine solution (2×50 ml). The organic extract was dried over anhydrousNa₂SO₄ and concentrated in vacuo to afford(2S,5R)5-(3,4-dimethoxy-phenyl)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (4.22, 0.012 mol, 100% yield). Analysis H¹ NMR (400MHz, CDCl₃): 6.95 (1H, s), 6.80 (2H, s), 4.67 (1H, m), 4.50 (1H, m),3.86 (6H, s), 2.52-1.89 (4H, m), 1.19 (9H, broad s). MS (LC-MS):Calculated for C18H25NO6 351.17, found 352.22 (M+H)⁺.

A solution of(2S,5R)₅-(3,4-dimethoxy-phenyl)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (2.50 g, 7.11 mmol, 1.0 equivalent),4-chloro-3-methoxyaniline (1.12 g, 7.11 mmol, 1.0 equivalent), PyBropcoupling reagent (3.98 g, 8.54 mmol, 1.2 equivalents), and DIEA (1.86ml, 10.7 mmol, 1.5 equivalents) in dichloromethane (35 ml) was allowedto stir at room temperature overnight. The reaction mixture wasconcentrated in vacuo. The resulting residue was dissolved in ethylacetate (100 ml) and washed with 1N NaOH (3×100 ml). The organic extractwas dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude oilwas filtered through a layer of silica and eluted with ethylacetate:hexanes (1:1). The filtrate was concentrated in vacuo to afford(2S,5R)2-(4-chloro-3-methoxy-phenylcarbamoyl)-5-(3,4-dimethoxy-phenyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (3.48 g, 7.09 mmol, 100% yield). Analysis H¹ NMR(400 MHz, CDCl₃): 7.59 (1H, broad s), 7.23 (1H, m), 6.85-6.60 (4H, m)4.64 (2H, m), 3.00 (3H, s), 3.83 (3H, s), 3.56 (3H, broad s), 2.62 (1H,broad m), 2.36 (1H, m), 2.11-1.89 (2H, m), 1.22 (9H, broad s). MS(LC-MS): Calculated for C25H31ClN2O6 490.19, found 491.15 (M+H)⁺.

(2S,5R)2-(4-Chloro-3-methoxy-phenylcarbamoyl)-5-(3,4-dimethoxy-phenyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (3.48 g, 7.09 mmol) was dissolved indichloromethane (100 ml) and cooled to 0° C. in an ice bath. TFA (30 ml)was then added slowly to the stirring solution. The reaction was allowedto stir and warm to room temperature overnight. The reaction mixture wasconcentrated in vacuo. The pH of the resulting residue was adjusted to 8with 1N NaOH and the product extracted into ethyl acetate. The extractwas then washed with brine solution (2×100 ml), dried over anhydrousNa₂SO₄ and concentrated in vacuo. The crude oil was chromatographed toafford (2S,5R)5-(3,4-dimethoxy-phneyl)-pyrrolidine-2-carboxylic acid(4-chloro-3-methoxy-phenyl)-amide (2.77 g, 7.09 mmol, 100% yield).Analysis H¹ NMR (400 MHz, CDCl₃): 10.02 (1H, broad s), 7.59 (1H, broads), 7.21 (1H, d), 7.03-6.82 (4H, m) 4.52-4.30 (2H, m), 3.90 (9H, m),2.70-1.88 (5H, m). MS (LC-MS): Calculated for C20H23ClN2O4 390.13, found391.16 (M+H)⁺.

(2S,5R)5-(3,4-Dimethoxy-phenyl)-pyrrolidine-2-carboxylic acid(4-chloro-3-methoxy-phenyl)-amide was dissolved in anhydrous THF andcooled to 0° C. in an ice bath. A 0.5M solution of alane complex intoluene (42.6 ml, 21.3 mmol, 3.0 equivalents) was added slowly and thereaction was allowed to stir and warm to room temperature overnight. Thereaction was quenched upon addition of ethyl acetate:methanol (1:1, 5ml). The resulting slurry was filtered through Celite and rinsed withethyl acetate. The filtrate was concentrated in vacuo to afford(2S,5R)(4-chloro-3-methoxy-phenyl)-[5-(3,3-dimethoxy-phenyl)-pyrrolidin-2-ylmethyl]-amine(1.80 g, 4.78 mmol, 67% yield). Analysis H¹ NMR (400 MHz, CDCl₃): 7.12(1H, d), 6.98-6.90 (3H, m), 6.23 (1H, s), 6.19 (1H, d) 4.39-4.15 (2H,m), 3.76-3.53 (1H, m), 3.30-2.97 (2H, m), 2.34-1.55 (6H, m). MS (LC-MS):Calculated for C20H25ClN2O3 376.16, found 377.21 (M+H)⁺.

A solution containing(2S,5R)(4-chloro-3-methoxy-phenyl)-[5-(3,3-dimethoxy-phenyl)-pyrrolidin-2-ylmethyl]-amine(1.80 g, 4.78 mmol, 1.0 equivalent), ethylbromoacetate (0.80 g, 4.78mmol, 1.0 equivalent), and DIEA (0.87 ml, 5.02 mmol, 1.05 equivalents)in acetonitrile (25 ml) was allowed to stir at room temperatureovernight. The reaction mixture was concentrated in vacuo. The resultingresidue was dissolved in ethyl acetate (50 ml) and washed with 1N NaOH(2×25 ml). The ethyl acetate extract was dried over anhydrous Na₂SO₄ andconcentrated in vacuo to afford a 2:1 mixture of regioisomers,(2S,5R)[2-[(4-chloro-3-methoxy-phenylamino)-methyl]-5-(3,4-dimethoxy-phenyl)-pyrrolidin-1-yl]-aceticacid ethyl ester and{4-chloro-3-methoxy-phenyl)-[5-(3,4-dimethoxy-phenyl)-pyrrolidin-2-ylmethyl]-amino}-aceticacid ethyl ester (2.21 g, 4.78 mmol, 100% yield). Analysis H¹ NMR (400MHz, CDCl₃): 7.12 (1H, d), 6.98 (1H, s), 6.90 (1H, d), 6.82 (1H, dd),6.74 (1H, m), 6.25-6.16 (2H, m), 4.64-4.50 (1H, m), 4.37, 3.60 (1H,split m), 4.27-3.90 (2H, m), 3.87 (9H, m), 3.46-3.00 (4H, m), 2.40-2.06(2H, m), 1.92-1.66 (2H, m), 1.34-1.14 (3H, m). MS (LC-MS): Calculatedfor C24H31ClN2O5 462.19, found 463.21 (M+H)⁺.

A solution of(2R,5S)[2-[(4-chloro-3-methoxy-phenylamino)-methyl]-5-(3,4-dimethoxy-phenyl)-pyrrolidin-1-yl]-aceticacid ethyl ester (125 mg, 0.27 mmol, 1.0 equivalent) in THF (5 ml) wascooled to 0° C. in an ice bath. NaH (16 mg, 0.40 mmol, 1.5 equivalents)was slowly added to the stirring solution. The reaction was allowed tostir and warm to room temperature overnight. The reaction mixture wascooled to room temperature and partitioned between ethyl acetate and 1NNaOH. The organic extract was dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The crude oil was loaded onto silica and rinsedwith hexanes to remove impurities. The product was eluted with ethylacetate and reconcentrated to afford(6R,9S)2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazin-3-one(80 mg, 0.19 mmol, 70% yield). Analysis H¹ NMR (400 MHz, CDCl₃): 7.39(1H, d), 6.95 (1H, s), 6.91 (2H, m), 6.83 (2H, d), 3.90 (9H, m), 3.71(2H, m), 3.58 (1H, d), 3.25 (1H, t), 2.96 (1H, d), 2.84 (1H, m), 2.29(1H, m), 2.08 (1H, m), 1.88 (1H, m), 1.71 (1H, m). MS (LC-MS):Calculated for C22H25ClN2O4 416.15, found 417.23 (M+H)⁺. Upon scale-up,heating (50° C.) is required for ring closure. Epimerization isobserved. Cis and trans isomers are separable by flash chromatography.

A solution of2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazin-3-one(80 mg, 0.19 mmol, 1.0 equivalents) in THF (2 ml) was cooled to 0° C. inan ice bath. A 0.5M solution of alane complex in toluene (1.14 ml, 0.57mmol, 3.0 equivalents) was slowly added and the reaction was allowed tostir for one hour. The reaction was quenched upon addition of ethylacetate:methanol (1:1, 1 ml). The resulting slurry was filtered througha layer of silica and concentrated in vacuo to afford(6R,9S)2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrrolo[1,2-a]pyrazine(compound 9; 49 mg, 0.12 mmol, 63% yield). Analysis H¹ NMR (400 MHz,CDCl₃): 7.20 (1H, d), 6.93 (1H, s), 6.90 (1H, d), 6.82 (1H, d), 6.52(1H, s), 6.49 (1H, d), 3.90 (9H, m), 3.73 (1H, d), 3.51 (1H, d), 3.21(1H, t), 2.93 (2H, m), 2.68 (1H, t), 2.44 (1H, m), 2.20 (2H, broad t),1.92 (1H, m), 1.65 (2H, m). MS (LC-MS): Calculated for C22H27ClN2O3402.17, found 403.23 (M+H)⁺. Chiral HPLC analysis revealed >98%enantiomeric purity.XI.(4-Trifluoromethyl-phenyl)-{4-[1-(4-Methoxy2,3-Dimethyl-phenyl)-ethyl]-piperazin-1-yl}-methanonevia Scheme K

A mixture of 2,3-dimethyl 4-methoxy benzaldehyde (1 g, 3.05 mmol), 1equivalent of piperazine-1-carboxylic acid tert-butyl ester (0.57 g,3.05 mmol), 1 equivalent of benzotriazole in ethanol was stirred at roomtemperature for 30 minutes. The solvent was removed and the reaction wasdried under vacuum. The reaction mixture was then dissolved in anhydrousTHF(20 ml) under N₂ at −78° C. Then 3 equivalents (3.05 ml) of methylmagnesium bromide (3M in THF) was added to the solution slowly. Thereaction mixture was kept at this temperature for 2 hours and warmed upto room temperature for overnight. The mixture was washed with 2N NaOHand water and extracted with ethyl acetate (2×30 ml). The combinedorganic layers were dried over MgSO₄. After removal of organic solvent,the residue was purified by a flash column on silica gel eluted with 1:1EtOAC:Hexane first, then with 10% MeOH(NH3) in dichloromethane.4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester was obtained as a yellow oil (0.59 g, 56%). Analysis H¹NMR (400 MHz, CDCl₃): 7.21 (1H, d), 6.68 (1H, d), 3.8 (3H, s), 3.58 (1H,q), 3.38 (3H, m), 2.45 (2H, m), 2.37 (2H, m), 2.24 (3H, s), 2.18 (3H,s), 1.43 (9H, s), 1.24 (3H, d). MS (LC-MS): Calculated for C20H32N2O3348.48, found 349.29 (M+).

To an ice chilled solution containing4-[1-(4-methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (0.4 g 1.38 mmol) and 10 ml dichloromethane, was addedtrifluoroacetic acid (2 ml) dropwise. The reaction was stirred at roomtemperature for 2 hours. The reaction was concentrated. The residue waspurified by flash chromatography on silica gel eluted with 10%MeOH(NH3)/dichloromethane.1-[1-(4-Methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine was obtained as ayellow oil (0.16 g 47%). Analysis H¹ NMR (400 MHz, CDCl₃): 7.23 (1H, d),6.69 (1H, d), 3.8 (3H, s), 3.55 (1H, q), 3.484 (2H, s), 2.838 (4H, m),2.47 (2H, m), 2.38 (2H, m), 2.271 (3H, s), 2.167 (3H, s), 1.26 (3H, d).MS (LC-MS): Calculated for C15H24N2O 248.36, found 249.25 (M+).1-[1-(4-Methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazine (0.02 g, 0.081mmole) was dissolved in anhydrous toluene and 1N NaOH (1:1) at roomtemperature. The 4-trifluoromtheyl benzoyl chloride (0.013 ml, 0.081mmole) was added into the reaction mixture. The reaction mixture wasstirred at room temperature for 30 minutes. The mixture was washed with1N NaOH, extracted with EtOAC. The combined organic layers were driedover MgSO₄. After removal organic solvent, the residue was purified bySCX column eluted with MeOH and 10% MeOH(NH3) in dichloromethane.(4-Trifluoromethyl-phenyl)-{4-[1-(4-Methoxy2,3-Dimethyl-phenyl)-ethyl]-piperazin-1-yl}-methanone(compound 10) was obtained as a pale yellow oil (0.010 g 30%). AnalysisH¹ NMR (400 MHz, CDCl₃): 7.65 (2H, d), 7.495 (2H, d), 7.19 (1H, d),6.689 (1H, d), 3.764 (3H, s), 3.682 (1H, q), 3.317 (2H, m), 2.506 (6H,m), 2.266 (3H, s), 2.164 (3H, s) 1.286 (3H, d). MS (LC-MS): Calculatedfor C23H27F3N2O2 420.47, found 421.26 (M+).XII.{5-[1-4-Methoxy-2,3-dimethyl-phenyl)-ethyl]-(1S,4S)-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-(4-trifluoromethyl-phenyl)-methanone(compound 11)

(1S,4S)-(−)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butylester (0.2 M 5% NMM/toluene, 0.100 mL, 0.020 mmol) was added to a ½ dramvial followed by 4-methoxy-2,3-dimethyl-benzaldehyde (0.2 M toluene,0.110 mL, 0.022 mmol) and benzotriazole (0.2 M EtOH, 0.110 mL, 0.022mmol). The vial was concentrated under reduced pressure at 40° C.(IR-Dancer). The resulting residue was dissolved in THF (0.20 mL,anhydrous), and the vial was capped under N₂ flow then treated withMeMgBr (1.0 M THF, 0.050 mL, 0.050 mmol). The vial was shaken at roomtemperature for 0.5 hours, then treated with HCl (4.0 M dioxane, 0.10mL). The vial was kept at 50° C. overnight, then basified with NaOH (10%aqueous (w/w), 0.50 mL) and treated with 4-trifluoromethyl benzoylchloride (0.2 M toluene, 0.15 mL, 0.03 mmol). The vial was shakenbriefly, then let stand at room temperature 0.5 hours, and was thendiluted with 1% Et₂NH in toluene (v/v, 0.50 mL). The vial was shakenvigorously, then let stand until the phases fully separated. The upperorganic phase was removed and deposited on a SCX SPE cartridge (0.5 gSCX, 3 mL cartridge). The cartridge was eluted to waste with 25% MeOH inEtOAc (v/v, 3 mL) and eluted to collect with EtOAc/MeOH/Et₃N (10:1:1v/v/v, 3 mL). The eluted solution was concentrated under N₂ flow, thenunder reduced pressure. The product (compound 11) was obtained as athick yellow oil (0.0057 g, 66%). Analysis: ¹HMR (400 MHz, CDCl₃):mixture of diastereomers/rotomers, diagnostic resonances: 3.821, 3.816,3.791, 3.782 (3H (combined), S (OCH₃)) MS (LCMS): Calculated forC24H27F3N2O2 432.20, found 433.17 [M+H]⁺.XIII. (±)-trans- and(±)-cis-2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine(compound 12)

(4-Chloro-3-methoxy-phenyl)-[5-(3,4-dimethoxy-phenyl)-pyrrolidin-2-ylmethyl]-amine(104 mg, 0.276 mmol; prepared as described above) was dissolved in asolution of CH₂Cl₂ (10 mL) and DMAP (74.1 mg, 0.667 mmol). The solutionwas cooled to 0° C. and oxalyl chloride (0.029 mL, 0.331 mmol) was addeddropwise. After 30 minutes, the reaction was quenched with the additionof ice water (10 mL). The organic phase was extracted with 1N HCl (20mL), 1N NaOH (20 mL), and brine (20 mL). The organic phase was driedover Na₂SO₄ and the solvent removed under reduced pressure. The crudeproduct((±)-cis-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine-3,4-dione)was purified by preparatory TLC eluting with hexanes/acetone (2:1) as aglassy colorless solid (49.7 mg, 41.8%). ¹H NMR (CDCl₃) δ 7.39 (d, J=8.7Hz, 1H, ArH), 7.08 (d, J=2.1 Hz, 1H, ArH), 6.85-6.81 (m, 3H, ArH), 6.75(dd, J=8.7, 2.1 Hz, 1H, ArH), 5.20 (d, J=9.0 Hz, 1H), 4.35-4.32 (m, 1H),4.16-3.95 (m, 2H), 3.90 (s, 3H, OCH₃), 3.89 (s, 3H, OCH₃), 3.86 (s, 3H,OCH₃), 2.46-2.40 (m, 1H), 2.17-1.87 (m, 2H). LCMS m/z 331 (M⁺+1, 100,2.07 min).

(±)-cis-2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine-3,4-dione(49.7 mg, 0.115 mmol) was dissolved in dry THF (10 mL) and BH₃.THF (1mL, 1 mmol) was added dropwise to the mixture, which was then heated atreflux overnight. The solution was cooled to 0° C. and MeOH (2 mL) wasadded dropwise. The solvent was removed by evaporation and the crudeproduct was dissolved in MeOH (10 mL) and 12N HCl (2 mL). The solutionwas refluxed for 4 hours. The reaction mixture was concentrated (−2 mL)followed by basification with 1N NaOH. The aqueous solution wasextracted with CH₂Cl₂ (3×25 mL). The combined organic extracts werewashed with brine, dried over Na₂SO₄, and concentrated under reducedpressure. The crude products were purified by preparatory TLC elutingwith CH₂Cl₂/MeOH (97:3) to yield the (±)-cis-(20.3 mg, 43.8%) and(±)-trans-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine(14.3 mg, 30.9%) with(±)-cis-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazineeluting further up the plate.(±)-trans-2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine¹H NMR (CDCl₃) δ 7.20 (d, J=8.7 Hz, 1H, ArH), 6.89-6.83 (m, 3H, ArH),6.47-6.40 (m, 2H, ArH), 4.16 (m, 1H), 3.95-3.84 (m, 1H), 3.90 (s, 3H,OCH₃), 3.88 (s, 6H, OCH₃), 3.58-3.46 (m, 1H), 3.41-3.36 (m, 1H),3.26-3.22 (m, 1H), 2.99-2.71 (m, 3H), 2.34-2.20 (m, 2H), 1.95-1.83 (m,1H), 1.64-1.54 (m, 1H). LCMS m/z 403 (M⁺+1, 100, 1.90 min).

XIV. Compounds 13-143

The compounds shown in TABLE I as compounds 13-143 were prepared viamethods A-M described above. TABLE I 1H NMR EX # STRUCTURE NAME (400MHz, CDCl3) MS Method 13

1-(4-bromo-3- methoxyphenyl)-4-(3,4- dimethoxybenzyl) piperazine7.32(1H, d), 6.89 (3H, m), 6.42(2H, m), 3.85(9H, m), 3.51 (2H, s),3.18(4H, t), 2.59(4H, t). 422.21 (M+) A 14

1-(4-bromo-3- methoxyphenyl)-4-(4- chlorobenzyl) piperazine7.38-7.25(5H, m), 6.44(1H, d), 6.40(1H, dd), 3.84(3H, s), 3.47(2H, s),3.2(4H, m), 2.60(4H, m) 397.0 (M+) A 15

1-[4-chloro-3- (trifluoromethyl) phenyl]-4-(3,4- dimethoxybenzyl)piperazine 415.2 (M+) A 16

1-(5-bromo-6- methoxypyridin-2-yl)- 4-(4-chlorobenzyl) piperazine7.45(1H, d), 7.30(5H, m), 6.04(1H, d), 3.90 (3H, s), 3.45(6H, m),2.47(4H, m) 398.0 (M+) A 17

1-(4-bromo-3- methoxyphenyl)-4-(3,4- dimethoxybenzyl)-1,4- diazepane7.24(1H, d), 6.90-6.80 (3H, m), 6.20(2H, m), 3.93(9H, m), 3.50(4H, m),2.77(2H, m), 2.62 (2H, m), 1.95(2H, m) 435.4 (M+) A 18

1-(3,4-dichlorophenyl)-4- (3,4-dimethoxybenzyl) piperazine 7.27(1H, d),6.94(1H, d), 6.91(1H, s), 6.83-6.85(m, 2H), 6.72(1H, dd), 3.90(d, 6H),3.17(2H, t), 2.57(2H, t) 382 (M+) A 19

1-(5-bromo-6- methoxypyridin-2-yl)-4- (4-methoxy-2,5- dimethylbenzyl)piperazine 7.55(1H, d), 7.03(1H, d), 6.64(1H, d), 6.03 (1H, d), 3.92(6H,d), 3.44(6H, d), 2.52(4H, d), 2.24(6H, dd). 420.22 (M+) A 20

1-(5-bromo-6- methoxypyridin-2-yl)-4- (4-methoxy-2,3- dimethylbenzyl)piperazine 7.55(1H, d), 7.01(1H, d), 6.68(1H, d), 6.08 (1H, d), 3.85(6H,d), 3.44(6H, m), 2.56(4H, m), 2.23(6H, d). A 21

1-(3-bromo-4- methoxybenzyl)-4-(5- bromo-6- methoxypyridin-2-yl)piperazine 7.56(2H, t), 7.21(1H, m), 6.83(1H, d), 6.06 (1H, d),3.88(6H, d), 3.47(6H, m), 2.55 (4H, m). 472.14 M+ A 22

4-(5-bromo-6- methoxypyridin-2-yl)-1- (3,4-dimethoxybenzyl)-2-methylpiperazine 7.51(1H, d), 6.85(3H, m), 6.06(1H, d), 4.05 (1H, m),3.923(2H, s), 3.905(9H, dd), 2.9(6H, m), 1.22(3H, d) 436.25 M+ A 23

1-(5-bromo-6- methoxypyridin-2-yl)-4- (4-methoxy-3- methylbenzyl)piperazine 7.49(1H, d), 7.08(2H, m), 6.79(1H, d), 6.06 (1H, d), 3.88(6H,d), 3.47(6H, m), 2.58(4H, m), 2.2(3H, s). 406.21 M+ A 24

4-{[4-(5-bromo-6- methoxypyridin-2- yl)piperazin-1- yl]methyl}-2-methoxyphenol 7.45(1H, d), 6.83(3H, m), 6.43(1H, s), 6.08 (1H, d),3.87(6H, d), 3.47(6H, m), 2.55(4H, m). 410.16 (M+2) A 25

3-{[4-(5-bromo-6- methoxypyridin-2- yl)piperazin-1- yl]methyl}-9-ethyl-9H-carbazole 8.07(2H, m), 7.43(5H, m), 7.21(1H, m), 6.08 (1H, m),4.37(2H, q), 3.92(3H, s), 3.75(2H, s), 3.5(4H, m), 2.59 (4H, m),1.43(3H, t). 479.24 M+ A 26

1-(4-bromo-3- methoxyphenyl)-4-(4- methoxy-2,5- dimethylbenzyl)piperazine 7.37(1H, d), 6.98(1H, s), 6.63(1H, s), 6.43 (1H, s), 6.38(1H,d), 3.83(6H, d), 3.44(2H, s), 3.17(4H, m), 2.59 (4H, m), 2.2(3H, s).419.23 M+ A 27

1-(4-bromo-3- methoxyphenyl)-4-(4- methoxy-2,3- dimethylbenzyl)piperazine 7.37(1H, d), 7.01(1H, d), 6.62(1H, d), 6.43 (1H, s), 6.38(1H,d), 3.82(6H, d), 3.44(2H, s), 3.17(4H, m), 2.59 (4H, m), 2.24(3H, s),2.16(3H, s). 419.21 M+ A 28

1-(3-bromo-4- methoxyphenyl)-4-(4- bromo-3-methoxyphenyl) piperazine7.57(1H, s), 7.36(1H, d), 7.24 (1H, d), 6.84 (1H, d), 6.43(1H, d),6.38(1H, d), 3.85(6H, d), 3.44(2H, s), 3.17 (4H, m), 2.59(4H, m). 471.07M+ A 29

4-{[4-(4-bromo-3- methoxyphenyl) piperazin-1-yl]methyl}- 2-methoxyphenol7.39(1H, d), 6.83(3H, m), 6.43(1H, s), 6.38 (1H, d), 3.83(6H, d),3.44(2H, s), 3.17(4H, m), 2.59(4H, m), 2.1(3H, s). 409.18 (M+2) A 30

1-(4-bromo-3- methoxyphenyl)-4[1- (3,4-dimethoxyphenyl)-ethyl]piperazine 7.39(1H, d), 6.84(3H, m), 6.24(2H, m), 3.82 (9H, m),3.49(1H, q), 3.18(4H, m), 2.60(4H, m), 1.29(3H, t). 436.3 M+ B 31

1-[4-chloro-3- (trifluoromethyl)phenyl]- 4-(4-methoxy-2,3-dimethylbenzyl) piperazine 7.34(1H, d), 7.0(3H, m), 6.67(1H, d), 3.85(3H, s), 3.44(2H, s), 3.19(4H, m), 2.59 (4H, m). 413.3 M+ A 32

1-(3-bromo-4- methoxybenzyl)-4-[4- chloro-3- (trifluoromethyl)-phenyl]piperazine 7.55(1H, s), 7.23(3H, m), 6.90(1H, d), 6.83 (1H, d),3.85(6H, s), 3.44(2H, s), 3.19(4H, m), 2.59(4H, m). 463.23 M+ A 33

4-({4-[4-chloro-3- (trifluoromethyl) phenyl]piperazin-1- yl}methyl)-2-methoxyphenol 7.35(1H, d), 7.14(1H, d), 6.93(4H, m), 3.85 (3H, s),3.44(2H, s), 3.19(4H, m), 2.59 (4H, m). A 34

1-(4-bromo-3- methoxyphenyl)-4-(4- methoxy-3- methylbenzyl)piperazine7.37(1H, d), 7.11(2H, d), 6.78(1H, d), 6.43(1H, s), 6.38(1H, d), 3.85(6H, d), 3.44(2H, s), 3.17(4H, m), 2.59(4H, m), 2.20(3H, s). 407.1 (M+2)A 35

3-{[4-(4-bromo-3- methoxyphenyl) piperazin-1-yl]methyl}-9-ethyl-9H-carbazole 8.07(3H, m), 7.38(6H, m), 6.42(1H, m), 4.84 (3H,s), 4.37(2H, q), 3.85(2H, s), 3.21(4H, m), 2.64(4H, m), 1.43 (3H, t).480.1 (M+2) A 36

1-[4-chloro-3- (trifluoromethyl)- phenyl]-4-(4-methoxy-3-methylbenzyl)piperazine 7.31(1H, m), 7.08(3H, m), 6.93(1H, m), 6.76 (1H,m), 4.54(1H, s), 3.82(3H, s), 3.47 (1H, s), 3.2(4H, m), 2.58(4H, m),2.21 (3H, s). 399.3 M+ A 37

5-bromo-4-methoxy-2- [4-(4-methoxy-2,3- dimethylbenzyl)piperazin-1-yl]pyrimidine 8.11(1H, d), 7.08(1H, d), 6.67(1H, d), 4.64(2H, s), 3.98(4H, m), 3.82(10H, m), 2.31 (3H, s), 2.2(3H, s). 421.24 M+A 38

5-bromo-2-[4-(3,4- dimethoxybenzyl) piperazin-1-yl]-4- methoxypyrimidineA 39

1-(4-bromo-3- methoxyphenyl)-4-(5,6- dimethoxy-2,3-dihydro-1H-indan-1-yl)piperazine 7.38(1H, d), 6.88(1H, s), 6.77(1H, s),6.38-6.47(2H, m) 477,449 (M+, M+2) B 40

4-[4-chloro-3- (trifluoromethyl)phenyl]- 1-(3,4-dimethoxybenzyl)piperidin-4-ol 7.85(1H, d), 7.61(1H, m), 7.46(1H, d), 6.80-6.90(3H, m),3.90(6H, d), 3.41(1H, m), 3.03(1H, m), 2.77 (1H, m), 2.21-2.42 (2H, m),1.96-2.19 (2H, m), 1.60-1.80 (2H, m), 1.40(3H, d) 444 M+ A 41

1-(5-bromo-6- methoxypyridin-2-yl)-4- [1-(3,4- dimethoxyphenyl)ethyl]piperazine 7.49(1H, d), 6.82(3H, m), 6.03(1H, d), 3.89 (9H, m),3.45(4H, m), 3.37(1H, q), 2.51(4H, m), 1.41(3H, d) B 42

2-(4-chloro-3-methoxy- phenyl)-6-(3,4- dimethoxy-phenyl)-octahydro-pyrido[1,2- a]pyrazin-8- one(racemic and R,S) 7.19(1H, d),6.86(3H, m), 6.46(1H, m), 6.41 (1H, dd), 3.91(3H, s), 3.89(3H, s),3.87(3H, s), 3.44(2H, m), 3.30 (2H, dd), 2.78(4H, m), 2.50(3H, m), 2.08(1H, td) 431.15 M+ B 43

(2S)-4-(5-bromo-6- methoxypyridin-2-yl)-1- (3,4-dimethoxybenzyl)-2-methylpiperazine 7.51(1H, d), 6.85(3H, m), 6.04(1H, d), 4.15 (1H, q),3.91(9H, m), 3.23(4H, m), 2.56(4H, m), 1.25(3H, d). 436.25 M+ A 44

1-(5-bromo-6- methoxypyridin-2-yl)-4- (5,6-dimethoxy-2,3-dihydro-1H-indan-1- yl)piperazine 7.51(1H, d), 6.90(1H, s), 6.75(1H, s),6.05 (1H, d), 4.38(1H, t), 3.88(9H, t), 3.50(4H, m), 2.78-2.90(2H, m),2.56(4H, m), 2.10 (2H, m) B 45

1-(4-bromo-3- methoxyphenyl)-4-[1-(4- methoxyphenyl) ethyl]piperazine7.34(1H, d), 7.23(2H, d), 6.86(2H, d), 6.44 (1H, d), 6.36(1H, d),3.85(3H, s), 3.80(3H, s), 3.42(1H, m), 3.16 (4H, m), 2.61(4H, m),1.41(3H, d). 405.24 M+ B 46

1-(1-benzo[1,3]dioxol-5- yl-ethyl)-4-(4-bromo-3- methoxy-phenyl)piperazine. 7.33(2H, m), 7.04(2H, m), 6.64(1H, d), 6.43 (1H, m),6.05(2H, s), 4.43(1H, m), 3.89(3H, s), 3.14(4H, m), 2.49 (4H, m),1.69(3H, d). 421.23 M+ B 47

1-(4-chloro-3- methoxyphenyl)-4-[1- (3,4-dimethoxyphenyl)ethyl]piperazine (racemic and R) 7.18(1H, d), 6.83-6.91 (3H, m),6.41-6.44 (2H, m), 3.87(9H, t), 3.23(1H, q), 3.15(4H, t)2.51-2.65(4H,m), 1.38(3H, d) 391 M+ B 48

1-(4-bromo-3- methoxyphenyl)-4-[1- (3,4-difluorophenyl) ethyl]piperazine7.36(2H, m), 6.97(2H, m), 6.64(1H, s), 6.42 (1H, d), 4.37(1H, m),3.98(3H, s), 4.46 (4H, m), 3.89(4H, m), 1.83(3H, d). 410.28 M+ B 49

4-{1-[4-(4-bromo-3- methoxyphenyl) piperazin-1-yl]ethyl}- 2-methylphenol7.78(2H, m), 7.32(1H, d), 7.07(2H, m), 6.73 (2H, m), 3.84(3H, s),3.17(1H, m), 3,16(4H, m), 2.54(4H, m), 1.41 (3H, d). 405.36 M+ B 50

1-(4-bromo-3- methoxyphenyl)-4-[1-(4- fluoro-3-methoxyphenyl)ethyl]piperazine 7.33(1H, d), 7.00(2H, m), 6.84(1H, m), 6.44 (1H, d),6.38(1H, dd), 3.90(3H, s), 3.86(3H, s), 3.33(1H, q), 3.17 (4H, t),2.65(2H, m), 2.53(2H, m), 1.37 (3H, d) 432.34 M+ C 51

1-(4-bromo-3- methoxyphenyl)-4-[1- (3,4-dimethoxyphenyl)-ethyl]piperazine (racemic and R) 7.18(1H, d), 6.83-6.91 (3H, m),6.41-6.44 (2H, m), 3.87(9H, t), 3.23(1H, q), 3.15(4H, t)2.51-2.65(4H,m), 1.38(3H, d) 391 M+ D 52

S-1-(4-chloro-3- methoxyphenyl)-4-[1- (3,4-dimethoxyphenyl)ethyl]piperazine 7.18(1H, d), 6.83-6.91 (3H, m), 6.41-6.44 (2H, m),3.87(9H, t), 3.23(1H, q), 3.15(4H, t)2.51-2.65(4H, m), 1.38(3H, d) 391M+ D 53

(3S)-1-(4-chloro-3- trifluoromethoxyphenyl)- 4-[1-(3,4-dimethoxy-benzyl)]-2-methyl- piperazine 7.5(1H, d), 7.363(3H, m), 6.985(2H, m),4.63(1H, d), 3.94(2H, m) 3.75(6H, d), 3.61 (1H, d), 3.18(2H, m),2.98(2H, s), 2.23(1H, s), 1.537(3H, d). 429.2 M+ B 54

1-(4-Bromo-3-methoxy- phenyl)-4-[1-(3,4- dimethoxy-phenyl)-propyl]-piperazine 7.36(1H, d), 6.81(3H, m), 6.42(1H, d), 6.39 (1H, dd),3.91(3H, s), 3.88(3H, s), 3.83(3H, s), 3.50(1H, m), 3.18 (4H, m),2.62(4H, m), 0.78(3H, t) 449.28 M+ B,C 55

1-(4-Chloro-3- trifluoromethyl-phenyl)- 4-[1-(3,4-dimethoxy-phenyl)-propyl]- piperazine 7.29(1h, d), 7.17(1H, d), 6.76-6.85(4H, m),3.83(6H, d), 3.18(4H, m), 2.57(m, 4H0, 1.97 (1H, m), 1.62(2H, m),0.78(3H, t) 443 M+ B 56

1-(4-Bromo-3-methoxy- phenyl)-4-[1-(3,4- dimethoxy-phenyl)-ethyl]-[1,4]diazepane 7.43(2H, m), 6.89(1H, m), 6.76(2H, m), 3.89 (9H,t), 2.68(10H, m), 1.21(3H, d). 450.36 M+ B 57

1-(4-Bromo-3-methoxy- phenyl)-4-[1-(3-fluoro-4- methoxy-phenyl)-ethyl]-[1,4]diazepane 7.63(2H, m), 7.21(2H, m), 6.86(2H, m), 4.46 (1H, m),3.89(6H, d), 2.68(10H, m), 1.41 (3H, d). 438.33 M+ B 58

(2S)-4-(4-chloro-3- trifluoromethyl-phenyl)- 1-(3,4-dimethoxy-benzyl)-2-methyl- piperazine 7.24(1H, d), 7.18(1H, d), 6.87(4H, m), 4.02(1H, m), 3.82(6H, d), 3.36(2H, m), 3.08(1H, d), 2.82(3H, m), 2.59 (1H,m), 2.22(1H, m) 1.21(3H, d). 429.26 M+ A 59

1-(4-bromo-3-methoxy- phenyl)-4-]1-(4-chloro- phenyl)-ethyl]-piperazine7.30(5H, m), 6.43(1H, d), 6.38 (1h, dd), 3.83 (3H, s), 3.38(1H, q),3.17(4H, t), 2.62(2H, m), 2.52(2H, m), 1.39(3H, d) B 60

{4-[1-(4-methoxy-2,3- dimethyl-phenyl)-ethyl]- [1,4]diazepan-1-yl}-(4-trifluoromethyl- phenyl)-methanone 1.30(3H, dd), 1.60(1H, dm), 1.88(1H,dm), 2.17(3H, d), 2.31(3H, d), 2.45-2.94(4H, m), 3.22(1H, dm), 3.36 (1H,t, J=8), 3.60(1H, dm), 3.81(3H, d), 3.84 (1H, m), 3.99(1H, t, J=8),6.67(1H, dd, J=11.2), 7.12(1H, dd, J=11.2), 7.38(1H, d, J=10.4),7.50(1H, d, J=10.8), 7.58 # (1H, d, J=11.2), 7.66(1H, d, J=11.2). 435.20M+ K 61

1-(4-chloro-3- trifluoromethyl-phenyl)- 4-(4,5-dimethoxy-indan-1-yl)-piperazine 7.31(1H, d), 7.15(1H, d), 7.03(1H, d), 6.93 (1H, dd),6.80(1H, d), 3.86(3H, s), 3.19(4H, m), 2.97(2H, m), 2.85 (2H, m),2.65(2H, m) 2.12(2H, q) 441.35 M+ B 62

2-(4-chloro-3- trifluoromethyl-phenyl)- 6-(3,4-dimethoxy-phenyl)-octahydro- pyrido[1,2-a]pyrazine 455.26 M+ H 63

1-(4-chloro-3-methoxy- phenyl)-4-[1-(4-methoxy- 2,3-dimethyl-phenyl)-ethyl]-piperazine 7.27(1H, t), 7.18(1H, d), 6.72(1H, d), 6.48 (1H, d),6.44(1H, dd) 3.86(3H, s), 3.82(3H, s), 3.64(1H, q), 3.14 (4H, m),2.65(2H, m), 2.56(2H, m), 2.29(3H, s), 2.18(3H, s), 1.32(3H, d) 389.2 M+C 64

(6R,10S)-2-(4-chloro-3- methoxy-phenyl)-6-(3- fluoro,4-methoxy-phenyl)-octahydro- pyrido[1,2-a]pyrazine 7.30-7.00(3H, m), 6.89(1H, t),6.42(2H, m), 3.88(3H, s), 3.86 (3H, s), 3.34(2H, m), 2.94(1H, d),2.74(2H, m), 2.62(1H, m), 2.31 (1H, t), 2.03(1H, m), 1.88-1.66(7H, m)405.12 M+ E 65

1-(4-chloro-3-methoxy- phenyl)-4-[1-(4-chloro- 3-methoxy-phenyl)-ethyl]piperazine 7.29(1H, d), 7.18(1H, d), 6.97(1H, m), 6.86 (1H, dd),6.47(1H, d), 6.42(1H, dd), 3.54(1H, q), 3.15(1H, t), 2.64 (2H, m),2.53(2H, m), 1.37(3H, d) 395.35 M+ B 66

2-(4-fluoro-3-methoxy- phenyl)-6-(3,4- dimethoxy-phenyl)-octahydro-pyrido[1,2- a]pyrazine 7.00-6.80(4H, m), 6.55(1H, dd),6.40(1H, dm), 3.89(3H, s), 3.87 (3H, s) 3.86(3H,s), 3.40-3.20(2H, m),2.95(1H, d), 2.784-2.52(3H, m), 2.30(1H, t), 2.8(1H, t), 1.90-1.40(6H,m) 401.45 M+ H 67

2-(4-fluoro-3- trifluoromethyl-phenyl)- 6-(3,4-dimethoxy-phenyl)-octahydro- pyrido[1,2-a]pyrazine 7.10-6.80(6H, m), 3.92(3H, s),3.86(3H, s), 3.44-3.30(2H, m), 2.94(1H, m), 2.80-2.58(3H, m), 2.32(1H,m), 2.02(1H, m), 1.90-1.40(6H, m) 439.48 M+ H 68

(2S)-4-(4-chloro-3- methoxy-phenyl)-1-(3,4- dimethoxy-benzyl)-2-methyl-piperazine 1.179(1H, s), 6.823 (3H, m), 6.468(2H, m), 4.17(1H,q), 3.872 (9H, t), 3.36(2H, m) 3.18(1H, d), 2.83(2H, m), 2.71(2H, m),2.53 (2H, m), 2.14(1H, m) 1.240(3H, m). 391.43 M+ A 69

1-(4-bromo-3-methoxy- phenyl)-4-[1-(4-methoxy- 2,5-dimethyl-phenyl)-ethyl]-piperazine 7.32(1H, d), 7.20(1H, s), 6.91(1H, s), 6.45 (1H, d),6.37(1H, dd), 3.85(3H, s), 3.53(1H, q), 3.12(4H, m), 2.66 (2H, m),2.54(2H, m), 2.30(3H, s), 2.23(3H, s), 2.21(3H, s), 1.32 (3H, d) 435.10M+ C 70

(4-chloro-phenyl)-{4-[1- (2,3-dimethyl-phenyl)- ethyl]-piperazin-1-yl}-methanone 7.36(4H, m), 7.26(1H, m), 7.05(2H, m), 3.67 (3H, m), 3.32(2H,m), 2.45(4H, m), 2.28(3H, s), 2.25(3H, s), 1.30 (3H, d). 357.18 M+ K 71

R-1-(4-fluoro-3- trifluoromethyl-phenyl)- 4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine 7.04(3H, m), 6.91(1H, s), 6.83(2H, m), 3.90(3H, s), 3.88(3H, s), 3.34(1H, q), 3.13(4H, t), 2.64(2H, m), 2.54 (2H,m), 1.39(3H, d) 413.23 M+ B 72

2-(4-chloro-3-methoxy- phenyl)-6-methoxy- naphthalen-2-yl)- octahydro-pyrido[1,2-a]pyrazine 7.70(2H, m), 7.51(1H, m), 7.15(3H, m), 6.42 (2H,m), 3.92(3H, s), 3.86(3H, s), 3.74(1H, t), 3.32(1H, d), 3.14 (1H, d),2.74(3H, m), 2.39(1H, m), 2.20-1.41(4H) 437.13 M+ E 73

2-(4-chloro-3-methyl- phenyl)-6-(3,4- dimethoxy-phenyl)- octahydro-pyrido[1,2-a]pyrazine 401.28 M+ H 74

R-1-(4-chloro-3- trifluoromethyl-phenyl)- 4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine 7.32(1H, d), 7.14(1H, d), 6.93(2H, m), 6.83(2H, m), 3.89(3H, s), 3.88(3H, s), 3.34(1H, q), 3.17(4H, t), 2.64 (2H,m), 2.53(2H, m), 1.38(3H, d) 429.23, 431.18 M+, M+2 B 75

1-(4-bromo-3-methoxy- phenyl)-4-[1-(4-ethoxy- 3-methoxy-phenyl)-ethyl]-piperazine 7.33(1H, d), 6.92(3H, m), 6.44(1H, d), 6.36 (1H, dd),4.09(2H, q), 3.88(3H, s), 3.85(3H, s), 3.33(1H, q), 3.16 (4H, t),2.65(2H, m), 2.54(2H, m), 1.46(3H, t), 1.39(3H, d) 449.38 M+ C 76

1-(4-bromo-3-methoxy- phenyl)-4-[1-(4-fluoro- 3-methoxy-phenyl)-ethyl]-piperazine 7.09(1H, d), 6.92(3H, m), 6.18(1H, d), 6.13 (1H, dd),3.88(3H, s), 3.85(3H, s), 3.83(3H, s), 3.77(1H, q), 3.15 (2H, m),2.77(2H, m), 1.38(3H, d) 365.39 M+ B 77

3-{1-[4-(4-bromo-3- methoxy-phenyl)- piperazin-1-yl]-ethyl}-2-chloro-6-methoxy- quinoline 8.28(1H, s), 7.90(1H, d), 7.36(1H, d), 7.33(1H, d), 7.08(1H, d), 6.46(1H, d), 6.39(1H, d), 4.03(1H, q), 3.92 (3H,s), 3.86(3H, s), 3.20(4H, m), 2.79(2H, m), 2.64(2H, m), 1.42 (3H, d)490.32, 492.32 M+, M+2 C 78

(4-chloro-phenyl)-{4-[1- (4-methoxy-2,3- dimethyl-phenyl)-ethyl]-piperazin-1-yl}- methanone 423.34 426.32 M+, M+2 K 79

(6S,10R)-2-(4-chloro-3- methoxy-phenyl)-6-(3,4- dimethoxy-phenyl)-octahydro- pyrido[1,2-a]pyrazine 7.19(1H, d), 6.90(2H, m), 6.45(1H, m),6.41 (1Hm dd), 3.91(3H, s), 3.89(3H, s), 3.87(3H, s), 3.41(2H, m), 2.97(1H, dd), 2.75(1H, m), 2.62(1H, m), 2.37(1H, m), 2.03(1H, dt),1.42-1.80(6H, m). 417.23 M+ E 80

1-(4-chloro-3-methoxy- phenyl)-4-[1-(4-fluoro-3- methoxy-phenyl)-ethyl]-piperazine 7.18(1H, d), 7.14(1H, dd), 7.03(1H, m), 6.90 (1H, m),6.47(1H, d), 6.40(1H, dd), 3.88 (3H, s), 3.86(3H, s), 3.35(1H, q),3.13(4H, t), 2.63(2H, m), 2.57 (2H, m), 1.35(3H, d) 379.25 M+ C 81

1-(4-bromo-3-methoxy- phenyl)-4-[1-(2,4,5- trimethyl-phenyl)-ethyl]-piperazine 7.33(1H, d), 7.18(1H, s), 6.59(1H, s), 6.45 (1H, d),6.38(1H, dd), 3.85(3H, s), 3.81(3H, s), 3.52(1H, q), 3.14 (4H, m),2.67(2H, m), 2.57(2H, m), 2.34(3H, s), 2.18(3H, s), 1.31 (3H, d) 417.12,419.12 M+, M+2 C 82

2-(4-methoxy-3-methyl- phenyl)-6-(3,4- dimethoxy-phenyl)- octahydro-pyrido[1,2-a]pyrazine 397.32 M+ C 83

1-(4-bromo-3-methoxy- phenyl)-4-[1-(6-methoxy- naphthalen-2-yl)-ethyl]-piperazine 7.70(3H, m), 7.50(1H, dd), 7.33(1H, d), 7.14 (2H, m),6.44(1H, d), 6.36(1H, dd), 3.92 (3H, s), 3.85(3H, s), 3.53(1H, q),3.16(4H, t), 2.69(2H, m), 2.58 (2H, m), 1.47(3H, d) 455.16, 457.15 M+,M+2 C 84

2-(4-chloro-3-methoxy- phenyl)-6-(3-methoxy- phenyl)-octahydro-pyrido[1,2-a]pyrazine 7.21(2H, m), 6.93(2H, m), 6.77(1H, dd), 6.46 (1H,d), 6.41(1H, dd), 3.86(3H, s), 3.81(3H, s), 3.44(1H, d), 3.40 (1H, d),3.00(1H, d), 2.80(2H, m), 2.60(1H, t), 2.29(1H, t), 2.95 (1H, dt),1.86-1.46 (6H, m) 387.23 M+ H 85

1-(4-bromo-3-methoxy- phenyl)-4-(4,5- dimethoxy-indan-1-yl)- piperazine7.46(1H, d), 7.02(1H, d), 6.81(1H, d), 6.04 (1H, d), 4.37(1H, t),3.88(3H, s), 3.85(3H, s), 3.47(4H, m), 2.93 (2H, m), 2.83(2H, m),2.59(4H, m), 2.10 (2H, q) 448.37 M+ B 86

1-(4-bromo-3-methoxy- phenyl)-4-[1-(3-fluoro-4- methoxy-phenyl)-ethyl]-piperazine B 87

2-(2,4-dibromo-5- methoxy-phenyl)-6-(3,4- dimethoxy-phenyl)- octahydro-pyrido[1,2-a]pyrazine H 88

7-(4-chloro-3-methoxy- phenyl)-4-(3,4- dimethoxy-phenyl)- decahydro-naphthalen-2-ol 7.20(1H, dd), 6.96-6.82(3H, m), 6.47(1H, d), 6.42(1H,dd), 4.32(1.5H, m), 4.00(1H, d), 3.88(3H, s), 3.87(6H, s), 3.65 (0.5H,m), 3.27-2.84 (5H, m), 2.68(1H, td), 2.09-1.94(3H, m), 1.62(2H, m) 89

1-(4-chloro-3- trifluoromethyl-phenyl)- 4-[1-(4-methoxy-2,3-dimethyl-phenyl)- ethyl]-piperazine 427.24 M+ C 90

1-(5-bromo-6-methoxy- pyridin-2-yl)-4-[1-(4- trifluoromethyl-phenyl)-ethyl]-piperazine 7.567(2H, d), 4.49(3H, m), 6.04(1H, d), 3.90 (3H, s),3.47(5H, m), 2.62-2.44(4H, m), 1.39(3H, d). 444.23 M+ B 91

2-(4-chloro-3-fluoro- phenyl)-6-(3,4- dimethoxy-phenyl)- octahydro-pyrido[1,2-a]pyrazine 405.26 M+ H 92

2-(3-methoxy-phenyl)-6- (3,4-dimethoxy-phenyl)- octahydro-pyrido[1,2-a]pyrazine H 93

R-1-(4-fluoro-3- methoxy-phenyl)-4-[1- (3,4-dimethoxy-phenyl)-ethyl]-piperazine 7.00-6.80(4H, m), 6.58(1H, m), 6.40(1H, m), 3.88(3H,s), 3.86 (3H, s), 3.85(3H, s), 3.35(1H, q), 3.10(4H, m), 2.64(2H, m),2.54 (2H, m), 1.38(3H, d) 375.17 M+ D 94

1-(4-chloro-3- trifluoromethyl-phenyl)- 4-[1-(4-chloro-3-methoxy-phenyl)- ethyl]-piperazine 7.31(2H, m), 7.14(1H, d), 6.94(2H,m), 6.84 (1H, dd), 3.91(3H, s), 3.35(1H, q), 3.18(4H, t), 2.64(2H, m),2.54 (2H, m), 1.37(3H, d) 433.34, 435.33 M+, M+2 B 95

2-(3-trifluoromethyl- phenyl)-6-(3,4- dimethoxy-phenyl)- octahydro-pyrido[1,2-a]pyrazine 421.28 M+ H 96

1-(4-chloro-3- trifluoromethyl-phenyl)- 4-[1-(4-methoxy-3-methyl-phenyl)- ethyl]-piperazine 413.25 M+ C 97

2-(4-chloro-3-methoxy- phenyl)-6-(3,4- dimethoxy-phenyl)-1,3,4,6,9,9a-hexahydro- 2H-pyrido[1,2-a]pyrazine 7.17(1H, d), 6.82(3H,m), 6.43(1H, d), 6.38 (1H, dd), 5.95(1H, m), 5.84(1H, dd), 4.33(1H, s),3.88(3H, s), 3.70 (3H, s), 3.85(3H, s), 3.43(1H, d), 3.40(1H, m),3.05(2H, m), 2.86 (1H, m), 2.24(3H, m) 415.18 M+ L 98

1-(4-bromo-3-methoxy- phenyl)-4-[1-(3-methoxy- phenyl)-ethyl]-piperazine7.33(1H, d), 7.24(1H, m), 6.92(2H, m), 6.80 (1H, dd), 6.44(1H, d),6.39(1H, dd), 3.84(3H, s), 3.81(3H, s), 3.36 (1H, q), 3.14(4H, t),2.65(2H, m), 2.55(2H, m), 1.39(3H, d) 405.20, 407.20 M+, M+2 C 99

4-(4-chloro-3- trifluoromethyl-phenyl)- 1-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperidine 7.53(1H, s), 7.40(1H, d), 7.31(1H, d), 6.89(1H, s), 6.83(2H, s), 3.91(3H, s), 3.88(3H, s), 3.40(1H, q), 3.19 (1H,d), 2.94(1H, d), 2.47(1H, m), 2.08(1H, m), 1.94(1H, m), 1.84-1.72(4H,m), 1.39(3H, d) 428.27 M+ B 100

1-(4-bromo-3-methoxy- phenyl)-4-[1-(4- trifluoromethyl-phenyl)-ethyl]-piperazine 7.59(2H, d), 7.46(2H, d), 7.33(1H, d), 6.44 (1H, d),6.38(1H, dd), 3.85(3H, d), 3.43(1H, q), 3.15(4H, m), 2.63-2.46(4H, m),1.39(3H, d). 445.21 M+. B 101

4-(4-fluoro-3- trifluoromethyl-phenyl)- 1-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine 7.04(3H, m), 6.85(3H, m), 3.87(3H, s), 3.80(3H, s), 3.37(1H, q), 3.11(4H, t), 2.63(2H, m), 2.57(2H, m), 1.40 (3H,d) 413.3 M+ C 102

(3,4-dichloro-phenyl)- {4-[1-(4-methoxy-2,3- dimethyl-phenyl)-ethyl]-piperazin- 1-yl}-methanone 7.45(2H, d), 7.26(2H, m), 6.64(1H, d), 3.80(3H, s), 3.76(3H, m), 3.36(2H, m), 2.43(4H, m), 2.26(3H, s), 2.16 (3H,s), 1.30(3H, d). 421.12 M+ K 103

(4-chloro-phenyl)-{4-[1- (4-methyl-naphthalen-1- yl)-ethyl]-piperazin-1-yl}-methanone 8.21(1H, d), 8.01(1H, dd), 7.51(2H, m), 7.43 (1H, d),7.33(3H, m), 7.26(2H, m), 4.07(1H, q), 3.68(2H, m), 3.28 (2H, m),2.68(3H, s), 2.45(4H, m), 1.48 (3H, d). 393.16 M+1 K 104

1-(4-chloro-3-methoxy- phenyl)-4-[1-(3-fluoro-4- methoxy-phenyl)-ethyl]-piperazine 7.17(1H, d), 7.12(1H, dd), 7.03(1H, d), 6.89 (1H, m),6.47(1H, d), 6.43(1H, dd), 3.88(3H, s), 3.86(3H, s), 3.35 (1H, q),3.13(4H, t), 2.63(2H, m), 2.52(2H, m), 1.35(3H, d) 379.25 M+ C 105

1-(4-bromo-3-methoxy- phenyl)-4-[1-(3-ethoxy- phenyl)-ethyl]-piperazine7.32(1H, d), 6.51(2H, d), 6.44(1H, d), 6.35 (2H, m), 3.85(3H, s),3.79(6H, s), 3.31(1H, q), 3.17(4H, t), 2.66 (2H, m), 2.55(2H, m),1.37(3H, d) 435.31, 437.29 M+, M+2 C 106

1-(5-{1-[4-(4-bromo-3- methoxy-phenyl)- piperazin-1-yl]-ethyl}-2-fluoro-phenyl)-ethanone 7.82(1H, dd), 7.57(1H, m), 7.37(1H, d), 7.10(1H, m), 6.43(1H, d), 6.39(1H, dd), 3.84 (3H, s), 3.45(1H, q), 3.18(4H,t), 2.63(5H, m), 2.53(2H, m), 1.39 (3H, d) 462.18 M+ M 107

8-bromo-3-(3,4- dimethoxy-benzyl)-9- methoxy-2,3,4,4a- tetrahydro-1H,6H-pyrazino[1,2- a]quinoxalin-5-one 9.16(1H, s), 6,98-6.80(5H, m), 6.31(1H,s), 3.88(3H, s), 3.86(3H, s), 3.84 (3H, s), 3.70-3.58 (2H, m), 3.54-3.44(3H, m), 3.00-2.82 (2H, m), 2.34-2.16 (2H, m) 462.18 M+ M 108

(2S)-4-(4-chloro-3- methoxy-phenyl)-[1-(3,4- dimethoxy-benzyl)-ethyl]-2-methyl- piperazine 7.19(1H, d), 6.97(3H, m), 4.83(1H, q), 4.43(1H, q), 3.89(9H, t), 3.27(1H, d), 3.08(2H, m), 2.92(2H, m), 2.64 (1H,m), 2.42(2H, m), 1.42(3H, d), 1.23 (3H, d). 405.21 (M+1). A 109

1-(4-chloro-3-methyl- phenyl)-4-[1-(4-methoxy- 3-methyl-phenyl)-ethyl]-piperazine 359.26 M+ C 110

1-(4-bromo-3-methoxy- phenyl)-4-[1-(3,5- dimethoxy-phenyl)-ethyl]-piperazine 7.32(1H, d), 6.52(2H, d), 6.44(1H, d), 6.38 (2H, m),3.85(3H, s), 3.79(6H, s), 3.32(1H, q), 3.16(4H, t), 2.65 (2H, m),2.56(2H, m), 1.37(3H, d) 435.29, 437.31 M+, M+2 C 111

1-(4-methoxy-3-methyl- phenyl)-4-[1-(4-methoxy- 2,3-dimethyl-phenyl)-ethyl]-piperazine 369.30 M+ C 112

3-{1-[4-(4-bromo-3- methoxy-phenyl)- piperazin-1-yl]-ethyl}-6-methoxy-quinoline 8.79(1H, s), 7.98(2H, m), 7.35(2H, m), 7.08 (1H, d),6.44(1H, d), 6.36(1H, dd), 3.93(3H, s), 3.85(s, 3), 3.64 (1H, q),3.18(4H, m), 2.71(2H, m), 2.59(2H, m), 1.50(3H, d) 456.45, 458.15 (M+) C113

(4-trifluoromethyl- phenyl)-{4-[1-(4- methoxy-2-methyl-phenyl)-ethyl]-piperazin- 1-yl}-methanone 7.67(2H, d), 7.51(2H, d),7.27(1H, d), 6.68 (2H, m), 3.78(5H, m), 3,58(1H, q), 3.32(2H, m),2.61-2.44(3H, m), 2.33(3H, s), 1.29 (3H, d). 407.20 M+1 K 114

1-(4-chloro-3-methyl- phenyl)-4-[1-(3,4- dimethoxy-phenyl)-ethyl]-piperazine 375.23 m+ C 115

1-(4-bromo-3-methoxy- phenyl)-4-[1-(3,4- diethoxy-phenyl)-ethyl]-piperazine 7.35(1H, d), 6.91(1H, s), 6.81(2H, s), 6.40 (1H, d),6.36(1H, dd), 4.12(4H, m), 3.85(3H, s), 3.31(1H, q), 3.15 (4H, t),2.62(2H, m), 2.52(2H, m), 1.44(6H, m), 1.37(3H, d) 463.37, 465.37 M+,M+2 C 116

1-(4-chloro-3-fluoro- phenyl)-4-[1-(4-methoxy- 2,3-dimethyl-phenyl)-ethyl]-piperazine 377.24 M+ C 117

2-(4-chloro-3-methoxy- phenyl)-6-(3-fluoro-4- methoxy-phenyl)-octahydro-pyrido[1,2- a]pyrazin-8-one 7.19(2H, m), 7.02(2H, d), 6.93(2H,t), 6.46 (1H, d), 6.40(1H, dd), 3.90(3H, s), 3.87(3H, s), 3.34(5H, m),2.43-2.82(6H, m), 2.09(1H, td) 419.2 M+ E 118

(4-trifluoromethyl- phenyl)-{4-[1-(4- methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazin- 1-yl}-methanone 7.63(2H, d), 7.51(2H, d),7.01(1H, m), 6.63 (1H, m), 4.08(2H, m), 3.81(6H, d), 3.38-3.06 (4H, m),2.67-2.43 (2H, m), 2.93(3H, d). 421.19 M+1. K 119

1-(4-chloro-3-methyl- phenyl)-4-[1-(4-methoxy- 2,3-dimethyl-phenyl)-ethyl]-piperazine 373.26 M+ C 120

4-trifluoromethyl- phenyl)-{4-[1-(4- methoxy-3-methyl-phenyl)-ethyl]-piperazin- 1-yl}-methanone 7.62(2H, d), 7.44(2H, d),7.06(2H, s), 6.78 (1H, d), 3.78(4H, m), 3.37(2H, m), 2.58-2.23(4H, m),2.21(3H, s), 2.04(1H, s), 1.23(3H, d). 407.24 M+1 K 121

(4-chloro-phenyl)-{4-[1- (4-methoxy-naphthalen- 1-yl)-ethyl]-piperazin-1-yl}-methanone 8.38-8.26(2H, dd), 7.48(3H, m), 7.41(4H, m), 6.78(1H,d), 4.06 (1H, q), 4.00(3H, s), 3.66(2H, m), 3.37(2H, m), 2.64-2.44(4H,m), 1.49(3H, d). 409.15 M+1 K 122

4-trifluoromethyl- phenyl)-{4-[1-(4- methoxy-2,3-dimethyl-phenyl)-propyl]- piperazin-1-yl}- methanone 7.66(2H, d), 7.44(2H, d),7.07(1H, d), 6.65 (1H, d), 3.81(3H, s), 3.78(2H, m), 3.50(1H, q),2.26(2H, m), 2.63 (1H, m), 2.44(2H, m), 2.27(1H, m), 2.22(3H, s),2.17(3H, s), 1.89 (1H, m), 1.78(1H, m), 0.7(3H, t). 435.26 M+1 K 123

(4-chloro-phenyl)-{4-[1- (4-methoxy-2,3- dimethyl-phenyl)-allyl]-piperazin-1-yl}- methanone 7.35(3H, m), 7.26(1H, s), 6.72(1H, d), 5.84(1H, q), 5.21-5.08 (2H, dd), 3.94(1H, d), 3.80(3H, s), 3.78(1H, m),2.45(3H, m), 2.25 (3H, s), 2.17(3H, s), 0.98(3H, m). 399.13 M+1 K 124

4-fluoro-phenyl)-{4-[1- (4-methoxy-2,3- dimethyl-phenyl)-ethyl]-piperazin-1-yl}- methanone 7.38(2H, m), 7.17(1H, d), 7.05(2H, m), 6.67(1H, d), 3.78(3H, s), 3.62(1H, q), 3.5(2H, m), 2.58-2.34(4H, m), 2.25(3,s), 2.18 (3H, s), 1.23(3H, d). 371.28 M+1 K 125

1-(4-chloro-3-fluoro- phenyl)-4-[1-(3,4- dimethoxy-phenyl)-ethyl]-piperazine 379.22 M+ C 126

4-bromo-3-methyl- phenyl)-{4-[1-(4- methoxy-2,3-dimethyl-phenyl)-ethyl]-piperazin- 1-yl}-methanone 7.54(1H, d), 7.25(1H, s),7.19(1H, d), 7.05 (1H, d), 6.68(1H, d), 3.79(3H, s), 3.66(3H, m),3.48(2H, s), 3.38 (2H, m), 2.29(2H, m), 2.39(3H, s), 2.62(3H, s),2.16(3H, s), 1.27 (3H, d). 447.15 M+2 K 127

1-(4-fluoro-3-methoxy- phenyl)-6-(3,4- dimethoxy-phenyl)- octahydro-pyrido[1,2-a]pyrazine 7.00-6.80(4H, m), 6.55(1H, dd), 6.40(1H, dm),3.98-3.80(1H, m), 3.88(3H, s), 3.86 (3H, s), 3.85(3H, s), 3.42(1H, m),3.14-2.78(6H, m), 2.00-1.80(2H, m), 1.78-1.38(4H, m) 401.26 M+ H 128

1-(4-methoxy-3-methyl- phenyl)-4-[1-(3-methyl- 4-methoxy-phenyl)-ethyl]-piperazine 355.30 M+ C 129

1-(4-methoxy-3-methyl- phenyl)-4-[1-(3,4- dimethoxy-phenyl)-ethyl]-piperazine 371.28 M+ C 130

1-(3,4-dimethoxy- phenyl)-4-[1-(4-methoxy- 2,3-dimethyl-phenyl)-ethyl]-piperazine 385.30 M+ C 131

1-(4-bromo-3-methoxy- phenyl)-4-[1-(6-methoxy- pyridin-3-yl)-ethyl]-piperazine 7.34(1H, d), 7.13(1H, s), 6.81(1H, s), 6.43 (1H, d), 6.38(1H,dd), 3.90(1H, m), 3.87(3H, s), 3.18(4H, t), 2.67 (4H, m), 1.43(3H, d)459.19, 461.19, 463.19 M+ C 132

R-1-(4-fluoro-3- trifluoromethyl-phenyl)- 4-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine 7.04(3H, m), 6.91(1H, s), 6.83(2H, m), 3.90(3H, s), 3.88(3H, s), 3.34(1H, q), 3.13(4H, t), 2.64(2H, m), 2.54 (2H,m), 1.39(3H, d) 413.20 M+ B 133

(3,4-dichloro-phenyl)- {4-[1-(4-methyl- naphthalen-1-yl)-ethyl]-piperazin-1-yl}- methanone 8.38-8.26(2H, dd), 7.48(3H, m), 7.41(3H, m),6.78(1H, d), 4.06 (1H, q), 4.00(3H, s), 3.66(2H, m), 3.37(2H, m),2.64-2.44(4H, m), 1.49(3H, d). 428.13 M+1 K 134

2-(4-chloro-3-methoxy- phenyl)-6-(6-methoxy- naphthalen-2-yl)-octahydro-pyrido[1,2- a]pyrazin-8-one 7.77(3H, m), 7.72(1H, d), 7.19(3H,m), 6.46 (1H, d), 6.41(1H, dd), 3.93(3H, 3H), 3.87 (3H, s), 3.50(2H, m),3.36(1H, d), 2.80(5H, m), 2.48(3H, m), 2.43(1H, td) 451.2 M+ E 135

1-(4-bromo-3-methoxy- phenyl)-4-{1-[4-(4- bromo-phenyl)-phenyl]-ethyl}-piperazine 7.57-7.40(9H, m), 7.33(1H, d), 6.82(1H, d), 6.42(d,1H0<6.37 (1H, dd), 3.83(3H, s), 3.52(1H, m), 3.22(m, 4H), 2.72(2H, m),2.65(2H, m), 1.43 (3H, d) B 136

(2R)-4-(4-chloro-3- methoxy-phenyl)-[1-(3,4- dimethoxy-benzyl)-ethyl]-2-methyl- piperazine 7.19(1H, d), 6.97(3H, m), 4.83(1H, q), 4.43(1H, q), 3.89(9H, t), 3.27(1H, d), 3.08(2H, m), 2.92(2H, m), 2.64 (1H,m), 2.42(2H, m), 1.42(3H, d), 1.23 (3H, d). 405.21 M+1 A 137

[6-(3,4-dimethoxy- phenyl)-octahydro- pyrido[1,2-a]pyrazin-2-yl]-(4-trifluoromethyl- phenyl)-methanone (mixture of rotamers)7.6-7.7(m, 2H); 7.4-7.5(m, 2H); 6.8 (m, 3H); 4.4-4.6(m, 1H); 3.9(s, 6H);1.0-3.4(m)F-19NMR: −63.27, −63.34 ppm (1:1 ratio). 449 (M+1) G 138

4-chloro-phenyl)-{4-[1- (4-methoxy-2,3- dimethyl-phenyl)-propyl]-piperazin- 1-yl}-methanone 7.38(4H, m), 7.12(1H, m), 6.63(1H,d), 3.78 (3H, s), 3.71(2H, H), 3.38(2H, m), 2.6-.2.43 (3H, m), 2.24(3H,s), 2.18(3H, s), 1.88(1H, m), 0.83(3H, t). 401.20 M+1 K 139

S-4-(4-chloro-3- trifluoromethyl-phenyl)- [1-(3,4-dimethoxy-benzyl)-ethyl]-piperazine B 140

1-(4-Bromo-3-methoxy- phenyl)-4-[1-(6-methoxy- pyridin-2-yl)-ethyl]-piperazine H-1 NMR: 7.54(1H, t), 7.33(1H, d), 6.93 (1H, d), 6.59(1H, d),6.45(1H, d), 6.38(1H, dd), 3.93(3H, s), 3.85 (3H, s), 3.64(1H, q),3.17(4H, t), 2.70(4H, m), 1.44(3H, d) 406.14, 408.15 (M+) C 141

3-{1-[4-(4-Bromo-3- methoxy-phenyl)- piperazin-1-yl]-ethyl}-6-fluoro-4-methyl-2H- chromen-2-ol 7.36(1H, m), 7.07-6.83(3H, m),6.46-6.37(2H, m), 6.36(0.5H, s), 6.13 (0.5H, s), 3.86, 3.85 (3H, s),3.62(0.5H, q), 3.43(0.5H, m), 3.14 (4H, m), 2.88(1H, m), 2.67(3H, m),2.13(3H, s), 2.08(3H, s), 1.39 (3H, m) 477.22, 479.20 M+, M+2 B 142

R-4-(4-chloro-3- trifluoromethyl-phenyl)- [1-(3,4-dimethoxy-benzyl)-ethyl]-piperazine B 143

2-(3,4-dimethoxy- phenyl)-6-(3,4- dimethoxy-phenyl)-octahydro-pyrido[1,2- a]pyrazine 413.32 M+ C

Example 2 Melanin Concentrating Hormone Receptor Binding Assay

This Example illustrates a standard assay of melanin concentratinghormone receptor binding that may be used to determine the bindingaffinity of compounds for the MCH receptor.

Total RNA was prepared from Cynomolgus macaque hypothalamus. Monkeyhypothalamic cDNA was prepared using random primers and reversetranscriptase according to standard methods. A cDNA encoding the monkeyMCH1 receptor was obtained via PCR amplification using the forward (5′)Primer of SEQ ID NO:3 and the reverse (3′) Primer of SEQ ID NO:4. Thefull length PCR product was initially cloned into the vector pCR 2.1(Invitrogen, Carlsbad, Calif.). The cDNA was reamplified using a forwardprimer engineered to include an optimal translation initiation site(Kozak sequence). A cDNA expression cassette fragment encoding themonkey MCH1 receptor was blunt end ligated into the PCR-SCRIPT vector(STRATAGENE, La Jolla, Calif.). The receptor sequence was excised fromthis vector using EcoRI and Not I and subcloned into the EcoRI/Not siteof PcDNA3.1 (INVITROGEN Corp., Carlsbad, Calif.). The MCH1 receptor DNAsequence is provided in SEQ ID NO:1, with the encoded amino acidsequence provided in SEQ ID NO:2.

HEK 293 cells (American Type Culture Collection, Manassas, Va.) werestably transfected with the MCH receptor expression vector via standardcalcium phosphate precipitation, and were grown to confluency(approximately 48-72 hours) in DMEM high glucose culture medium (catalog#10-017-CV, MEDIATECH, Herndon, Va.) supplemented with 10% fetal bovineserum and 25 mM HEPES, and 500 μg/ml G418, for 48-72 hours at 37-C, 5%CO₂. The cells were pelleted by gentle centrifugation. Cell pellets werewashed twice with cold PBS, harvested in cold PBS containing 5 mM EDTA,and stored at −80° C.

At the time of assay, pellets were thawed by addition of wash buffer (25mM Hepes with 1.0 mM CaCl₂, 5.0 mM MgCl₂, 120 mM NaCl, PH7.4) andhomogenized for 30 seconds using a BRINKMAN POLYTRON, setting 5. Cellswere centrifuged for 10 minutes at 48,000×g. The supernatant wasdiscarded and the pellet was resuspended in fresh wash buffer, andhomogenized again. An aliquot of this membrane homogenate was used todetermine protein concentration via the Bradford method (BIO-RAD ProteinAssay Kit, #500-0001, BIO-RAD, Hercules, Calif.). By this measure, a1-liter culture of cells typically yields 50-75 mg of total membraneprotein. The homogenate was centrifuged as before and resuspended to aprotein concentration of 333 μg/ml in binding buffer (Wash buffer+0.1%BSA and 1.0 μM final phosphoramidon) for an assay volume of 50 μgmembrane protein/150 ul binding buffer. Phosphoramidon was from SIGMABIOCHEMICALS, St. Louis, Mo. (cat# R-7385).

Competition binding assays were performed at room temperature in Falcon96 well round bottom polypropylene plates. Each assay well contained 150μl of MCH receptor containing membranes prepared as described above, 50μl ¹²⁵I-Tyr MCH, 50 μl binding buffer, and 2 μl test compound in DMSO.¹²⁵I-Tyr MCH (specific activity=2200 Ci/mMol) is purchased from NEN,Boston, Mass. (Cat # NEX 373) and was diluted in binding buffer toprovide a final assay concentration of 30 pM.

Non-specific binding was defined as the binding measured in the presenceof 1 μM unlabeled MCH. MCH is purchased from BACHEM U.S.A., King ofPrussia, Pa. (cat # H-1482). Assay wells used to determine MCH bindingcontained 150 μl of MCH receptor containing membranes, 50 μl ¹²⁵I-TyrMCH, 25 μl binding buffer, and 25 μl binding buffer.

Assay plates were incubated for 1 hour at room temperature. Membraneswere harvested onto WALLAC™ glass fiber filters (PERKIN-ELMER,Gaithersburg, Md.) which were pre-soaked with 1.0% PEI(polyethyleneimine) for 2 hours prior to use. Filters were allowed todry overnight, and then counted in a WALLAC 1205 BETA PLATE counterafter addition of WALLAC BETA SCINT™ scintillation fluid.

For saturation binding, the concentration of ¹²⁵I-Tyr MCH was variedfrom 7 to 1,000 pM. Typically, 11 concentration points were collectedper saturation binding curve. Equilibrium binding parameters weredetermined by fitting the allosteric Hill equation to the measuredvalues with the aid of the computer program FitP™ (BIOSOFT, Ferguson,Mo.). For the compounds described herein, K_(i) values were below 1micromolar, preferably below 500 nanomolar, more preferably below 100nanomolar.

Example 3 Calcium Mobilization Assay

This Example illustrates a representative functional assay formonitoring the response of cells expressing melanin concentratinghormone receptors to melanin concentrating hormone. This assay can alsobe used to determine if test compounds act as agonists or antagonists ofmelanin concentrating hormone receptors.

Chinese Hamster Ovary (CHO) cells (American Type Culture Collection;Manassas, Va.) were stably transfected with the MCH expression vectordescribed in Example 2 via calcium phosphate precipitation, and weregrown to a density of 15,000 cells/well in FALCON™ black-walled,clear-bottomed 96-well plates (#3904, BECTON-DICKINSON, Franklin Lakes,N.J.) in Ham's F12 culture medium (MEDIATECH, Herndon, Va.) supplementedwith 10% fetal bovine serum, 25 mM HEPES and 500 μg/mL (active) G418.Prior to running the assay, the culture medium was emptied from the 96well plates. Fluo-3 calcium sensitive dye (Molecular Probes, Eugene,Oreg.) was added to each well (dye solution: 1 mg FLUO-3 AM, 440 μL DMSOand 440 μl 20% pluronic acid in DMSO, diluted 1:4, 50 μl dilutedsolution per well). Plates were covered with aluminum foil and incubatedat 37° C. for 1-2 hours. After the incubation, the dye was emptied fromthe plates, cells were washed once in 100 μl KRH buffer (0.05 mM KCl,0.115 M NaCl, 9.6 mM NaH₂PO₄, 0.01 mM MgSO₄, 25 mM HEPES, pH 7.4) toremove excess dye; after washing, 80 μl KRH buffer was added to eachwell.

Fluorescence response was monitored upon the addition of either humanMCH receptor or test compound by a FLIPR™ plate reader (MolecularDevices, Sunnyvale, Calif.) by excitation at 480 nM and emission at 530nM.

In order to measure the ability of a test compound to antagonize theresponse of cells expressing MCH receptors to MCH, the EC₅₀ of MCH wasfirst determined. An additional 20 μl of KRH buffer and 1 μl DMSO wasadded to each well of cells, prepared as described above. 100 μl humanMCH in KRH buffer was automatically transferred by the FLIPR instrumentto each well. An 8-point concentration response curve, with final MCHconcentrations of 1 nM to 3 μM, was used to determine MCH EC₅₀.

Test compounds were dissolved in DMSO, diluted in 20 μl KRH buffer, andadded to cells prepared as described above. The 96 well platescontaining prepared cells and test compounds were incubated in the dark,at room temperature for 0.5-6 hours. It is important that the incubationnot continue beyond 6 hours. Just prior to determining the fluorescenceresponse, 100 μl human MCH diluted in KRH buffer to 2×EC₅₀ wasautomatically added by the FLIPR instrument to each well of the 96 wellplate for a final sample volume of 200 μl and a final MCH concentrationof EC₅₀. The final concentration of test compounds in the assay wellswas between 1 μM and 5 μM. Typically, cells exposed to one EC₅₀ of MCHexhibit a fluorescence response of about 10,000 Relative FluorescenceUnits. Antagonists of the MCH receptor exhibit a response that issignificantly less than that of the control cells to the p≦0.05 level,as measured using a parametric test of statistical significance.Typically, antagonists of the MCH receptor decreased the fluorescenceresponse by about 20%, preferably by about 50%, and most preferably byat least 80% as compared to matched controls.

The ability of a compound to act as an agonist of the MCH receptor wasdetermined by measuring the fluorescence response of cells expressingMCH receptors, using the methods described above, in the absence of MCH.Compounds that cause cells to exhibit fluorescence above background areMCH receptor agonists.

Example 4 Determination of Dopamine D₂ and D₄ Receptor Binding Activity

This Example illustrates a representative standard assay for determiningthe binding affinity of compounds to dopamine D₄ and D₂ receptors.

Pellets of Chinese hamster ovary (CHO) cells containing recombinantlyexpressing primate D₂, human D₄ dopamine receptors were used for theassays. The sample was homogenized in 100 volumes (w/vol) of 0.05 M TrisHCl buffer containing 120 mM NaCl, 5 mM MgCl₂ and 1 mM EDTA at 4° C. andpH 7.4. The sample was then centrifuged at 30,000×g and resuspended andrehomogenized. The sample was then centrifuged as described and thefinal tissue sample was frozen until use. The tissue was resuspended1:20 (wt/vol) in 0.05 M Tris HCl buffer containing 120 mM NaCl.

Incubations for dopaminergic binding are carried out at 25° C. andcontain 0.4 ml of tissue sample, 0.1 nM ³H-YM 09151-2 (Nemonapride,cis-5-Chloro-2-methoxy-4-(methylamino)-N-(2-methyl-2-(phenylmethyl)-3-pyrrolidinyl)benzamide)and the compound of interest in a total incubation of 1.0 ml.Nonspecific binding was defined as that binding found in the presence of1 micromolar spiperone; without further additions, nonspecific bindingwas less than 20% of total binding.

Example 5 MDCK Cytotoxicity Assay

This Example illustrates the evaluation of compound toxicity using aMadin Darby canine kidney (MDCK) cell cytoxicity assay.

1 μL of test compound is added to each well of a clear bottom 96-wellplate (PACKARD, Meriden, Conn.) to give final concentration of compoundin the assay of 10 micromolar, 100 micromolar or 200 micromolar. Solventwithout test compound is added to control wells.

MDCK cells, ATCC no. CCL-34 (American Type Culture Collection, Manassas,Va.), are maintained in sterile conditions following the instructions inthe ATCC production information sheet. Confluent MDCK cells aretrypsinized, harvested, and diluted to a concentration of 0.1×10⁶cells/ml with warm (37° C.) medium (VITACELL Minimum Essential MediumEagle, ATCC catalog # 30-2003). 100 μL of diluted cells is added to eachwell, except for five standard curve control wells that contain 100 μLof warm medium without cells. The plate is then incubated at 37° C.under 95% O₂, 5% CO₂ for 2 hours with constant shaking. Afterincubation, 50 μL of mammalian cell lysis solution is added per well,the wells are covered with PACKARD TOPSEAL stickers, and plates areshaken at approximately 700 rpm on a suitable shaker for 2 minutes.

Compounds causing toxicity will decrease ATP production, relative tountreated cells. The PACKARD, (Meriden, Conn.) ATP-LITE-M LuminescentATP detection kit, product no. 6016941, is generally used according tothe manufacturer's instructions to measure ATP production in treated anduntreated MDCK cells. PACKARD ATP LITE-M reagents are allowed toequilibrate to room temperature. Once equilibrated, the lyophilizedsubstrate solution is reconstituted in 5.5 mL of substrate buffersolution (from kit). Lyophilized ATP standard solution is reconstitutedin deionized water to give a 10 mM stock. For the five control wells, 10μL of serially diluted PACKARD standard is added to each of the standardcurve control wells to yield a final concentration in each subsequentwell of 200 nM, 100 nM, 50 nM, 25 nM and 12.5 nM. PACKARD substratesolution (50 μL) is added to all wells, which are then covered, and theplates are shaken at approximately 700 rpm on a suitable shaker for 2minutes. A white PACKARD sticker is attached to the bottom of each plateand samples are dark adapted by wrapping plates in foil and placing inthe dark for 10 minutes. Luminescence is then measured at 22° C. using aluminescence counter (e.g., PACKARD TOPCOUNT Microplate Scintillationand Luminescence Counter or TECAN SPECTRAFLUOR PLUS), and ATP levelscalculated from the standard curve. ATP levels in cells treated withtest compound(s) are compared to the levels determined for untreatedcells. Cells treated with 10 μM of a preferred test compound exhibit ATPlevels that are at least 80%, preferably at least 90%, of the untreatedcells. When a 100 μM concentration of the test compound is used, cellstreated with preferred test compounds exhibit ATP levels that are atleast 50%, preferably at least 80%, of the ATP levels detected inuntreated cells.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention.

Description of the Sequence Listing

-   SEQ ID NO:1 Cynomolgus macaque MCH 1 R DNA sequence-   SEQ ID NO:2 Cynomolgus macaque MCHIR amino acid sequence-   SEQ ID NO:3 5′Cynomolgus macaque MCH1R primer-   SEQ ID NO:4 3′Cynomolgus macaque MCH1R primer

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein: V is a bond or—(C═O)—; W is nitrogen, CH, C—OH or C—CN; X is selected from halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy; Y and Z are each; n is1 or 2; R₁ and R₂ are each independently selected from hydrogen,halogen, (C₁-C₆)alkyl, halo(CB-C₆)alkyl and (C₁-C₆)alkoxy; with theproviso that if R₁ and R₂ are hydrogen, then V is —(C═O); R₃ is joinedwith R₆ to form a heterocyclic group having 5 or 6 ring members, withone ring member being nitrogen and remaining ring atoms being carbon,wherein the heterocyclic group is substituted with 0, 1 or 2substituents independently chosen from hydrogen, halogen, cyano,hydroxy, oxo, oxime, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkanoyl,C₁-C₆alkanoyloxy, C₁-C₆alkoxycarbonyl, halo(C₁-C₆)alkyl andhalo(C₁-C₆)alkoxy; R₄ is hydrogen, (C₁-C₆)alkyl or halo(C₁-C₆)alkyl; R₅is independently selected at each occurrence from hydrogen, halogen,hydroxy, nitro, cyano, amino, oxo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,mono- and di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl; R₇ selected fromhydrogen, halogen, (C₁-C₆alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy; or(ii) joined with R₈ or R₁₂ to form a fused phenyl ring; R₈ is selectedfrom hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and(C₁-C₆)alkoxy; or (ii) joined with R₇ or R₁₁ to form a fused phenylring; U is CR₉; T is CR₁₀; R₉ is selected from hydrogen, halogen,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy; or (ii) joined withR₁₀ or R₁₁ to form a fused phenyl ring; R₁₀ is selected from hydrogen,halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and (C₁-C₆)alkoxy; or (ii)joined with R₃, R₈ or R₉ to form a fused phenyl ring; R₁₁ is selectedfrom hydrogen, halogen, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl and(C₁-C₆)alkoxy; or (ii) joined with R₈ or R₉ to form a fused phenyl ring;R₁₂ is independently selected at each occurrence from hydrogen, halogen,hydroxy, nitro, cyano, amino, oxo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,mono- and di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl; or (ii) joinedwith R₇ to form a fused phenyl ring.
 2. A compound or salt according toclaim 1, wherein W is nitrogen.
 3. A compound or salt according to claim1, wherein n is
 1. 4-10. (cancelled).
 11. A compound or salt accordingto claim 1, wherein X is a halogen, (C₁-C₃)alkyl, halo (C₁-C₃)alkyl, or(C₁-C₃)alkoxy.
 12. A compound or salt according to claim 11, wherein R₁is hydrogen.
 13. A compound or salt according to claim 11, wherein R₁₁is methoxy.
 14. A compound or salt according to claim 11, wherein R₁₁ ishalogen.
 15. A compound or salt according to claim 1, wherein U is CR₉and R₇, R₈, and R₉ are each independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆ alkoxy and halogen.
 16. A compound or salt according toclaim 1, wherein R₁₁ is halogen and R₈ is (C₁-C₆)alkoxy.
 17. A compoundor salt according to claim 1, wherein each R₅ is independently hydrogenor methyl.
 18. (cancelled).
 19. A compound or salt according to claim 1,wherein V is a bond.
 20. A compound or salt according to claim 1,wherein V is —(C═O)—.
 21. A compound or salt according to claim 1, ofthe formula:

wherein: A and B are each independently selected from CR₁₃ and CHR₁₃,wherein R₁₃ is independently selected at each occurrence from hydrogen,halogen, cyano, hydroxy, oxo, oxime, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl,halo(C₁-C₆)alkyl and halo(C₁-C₆)alkoxy; R₄ is hydrogen or methyl; thebond between A and B is a single bond or a double bond; R₅ isindependently selected at each occurrence from hydrogen and methyl; andR₁₁ is hydrogen, halogen, or methoxy.
 22. A compound or salt accordingto claim 21, wherein A and B are each CR₁₃.
 23. (cancelled).
 24. Acompound or salt according to claim 21, wherein R₇, R₈ and R₉ are eachindependently selected from hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy andhalogen. 25-27. (cancelled).
 28. A compound or salt according to claim1, wherein the compound is selected from the group consisting of:2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-trifluoromethyl-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-methoxy-phenyl)-6-(3-fluoro,4-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-fluoro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-fluoro-3-trifluoromethyl-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-methoxy-phenyl)-6-methoxy-naphthalen-2-yl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-methyl-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-methoxy-3-methyl-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-methoxy-phenyl)-6-(3-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(2,4-dibromo-5-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(3,4-dimethoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-fluoro-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;1-(4-fluoro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-ol;2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one;2-(4-chloro-3-methoxy-phenyl)-6-(3-fluoro-4-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one;2-(4-chloro-3-methoxy-phenyl)-6-(6-methoxy-naphthalen-2-yl)-octahydro-pyrido[1,2-a]pyrazin-8-one;2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrrolo[1,2-a]pyrazine;2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-1,3,4,6,9,9a-hexahydro-2H-pyrido[1,2-a]pyrazine;and2-(4-chloro-3-methoxy-phenyl)-6-(3-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-ol.29. A compound or salt according to claim 1, wherein the compound is[6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-(4-trifluoromethyl-phenyl)-methanone.30. (cancelled).
 31. A compound or salt according to claim 1, whereinthe compound is selected from the group consisting of:(6R,10S)-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one;(6R,10S)-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine;(6R,9S)-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrrolo[1,2-a]pyrazine;(6R,10S)-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-ol;(6R,10S)-[6-(3,4-dimethoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-(4-trifluoromethyl-phenyl)-methanone;and (6R,10S)-2-(4-chloro-3-methoxy-phenyl)-6-(3-fluoro,4-methoxy-phenyl)-octahydro-pyrido[1,2-a]pyrazine. 32-35. (cancelled).36. A pharmaceutical composition, comprising a compound or saltaccording to claim 1, in combination with a physiologically acceptablecarrier or excipient.
 37. pharmaceutical composition according to claim36, wherein the composition is formulated as an injectible fluid, anaerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermalpatch. 38-55. (cancelled).
 56. A method for treating obesity in apatient, comprising administering to a patient in need of such treatmentan effective amount of a compound or salt according to claim
 1. 57. Amethod according to claim 56, wherein the compound or salt isadministered orally.
 58. A method according to claim 56, wherein thepatient is a human.
 59. A method according to claim 56, wherein thepatient is a dog or a cat. 60-63. (cancelled).
 64. A compound or saltaccording to claim 21, wherein: A and B are CH₂; R₄ is hydrogen; R₇, R₈,R₉ and R₁₁ are each independently selected from hydrogen, C₁-C₆alkyl,C₁-C₆alkoxy and halogen; n is 1; and each R₅ and R₁₂ are hydrogen.
 65. Acompound or salt according to claim 64, wherein: Y and Z are each CH; Xis halogen, methoxy or trifluoromethyl; and R₁ and R₂ are independentlychosen from hydrogen, halogen, methyl, methoxy and di- andtri-fluoromethyl.
 66. A compound or salt according to claim 65, wherein:R₇ is hydrogen; R₉ is hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy or halogen; andR₈ and R₁₁ are independently selected from C₁-C₆alkyl, C₁-C₆alkoxy andhalogen.
 67. A compound or salt according to claim 66, wherein: R₁ ishydrogen; and R₂ is halogen, methyl, methoxy or di- or tri-fluoromethyl.68. A compound or salt according to claim 64, wherein W is N.
 69. Acompound or salt according to claim 1, wherein R₇ is hydrogen, R₈ ismethoxy, R₉ is hydrogen, R₁₀ is hydrogen and R₁₁ is methoxy.
 70. Acompound or salt according to claim 1, wherein R₇ is hydrogen, R₈ is ahalogen, R₉ is hydrogen, R₁₀ is hydrogen and R₁₁ is methoxy.
 71. Acompound or salt according to claim 21, wherein R₇ is hydrogen, R₈ ismethoxy, R₉ is hydrogen, R₁₀ is hydrogen and R₁₁ is methoxy.
 72. Acompound or salt according to claim 71, wherein W is N and n is
 1. 73. Acompound or salt according to claim 21, wherein R₇ is hydrogen, R₈ is ahalogen, R₉ is hydrogen, R₁₀ is hydrogen and R₁₁ is methoxy.
 74. Acompound or salt according to claim 73, wherein W is N and n is 1.